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Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors

Sponsor
Genentech, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT00996892
Collaborator
(none)
178
Enrollment
6
Locations
6
Arms
51.9
Duration (Months)
29.7
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, multicenter, Phase Ib dose-escalation study designed to assess the safety, tolerability and pharmacokinetics of oral dosing of cobimetinib and pictilisib administered in combination in patients with locally advanced or metastatic solid tumors.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
178 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors
Study Start Date :
Nov 1, 2009
Actual Primary Completion Date :
Mar 1, 2014
Actual Study Completion Date :
Mar 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose Escalation Stage 1: Cobimetinib + Pictilisib

Participants will receive cobimetinib capsules (at a starting dose of 20 milligrams [mg]) and pictilisib capsules (at a starting dose of 80 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify maximum tolerated dose (MTD) or potential recommended Phase 2 dose (RP2D). Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

Drug: Cobimetinib
Repeated oral dosing.
Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•
    Experimental: Dose Escalation Stage 1A: Cobimetinib + Pictilisib

    Participants will receive cobimetinib capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Doses will be increased to identify MTD or potential RP2D.Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

    Drug: Cobimetinib
    Repeated oral dosing.
    Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•
    Experimental: Dose Escalation Stage 1B: Cobimetinib + Pictilisib

    Participants will receive cobimetinib capsules (at a starting dose of 40 mg) and pictilisib capsules (at a starting dose of 130 mg) from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets.

    Drug: Cobimetinib
    Repeated oral dosing.
    Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•
    Experimental: Dose Expansion Stage 2: Cobimetinib + Pictilisib

    Participants will received cobimetinib capsules and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; and KRAS mutant colorectal cancer (CRC).

    Drug: Cobimetinib
    Repeated oral dosing.
    Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•
    Experimental: Dose Expansion Stage 2A: Cobimetinib + Pictilisib

    Participants received cobimetinib capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1A. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.

    Drug: Cobimetinib
    Repeated oral dosing.
    Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•
    Experimental: Dose Expansion Stage 2B: Cobimetinib + Pictilisib

    Participants will receive cobimetinib capsules and pictilisib capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles, at doses identified as MTD/potential RP2D from Stage 1B. Participants will be off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion meets. This indication specific cohort will include participants with KRAS mutant endometrioid carcinoma.

    Drug: Cobimetinib
    Repeated oral dosing.
    Other Names:
  • GDC-0973
  • XL518

    • Drug: Pictilisib
    Repeated oral dosing.
    Other Names:
  • GDC-0941

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B [Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28]

      DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity, excluding the following: Grade 3 nausea, vomiting, or diarrhea that resolved to Grade ≤1 within 7 days, Grade 3 rash or Grade ≥3 fatigue that resolved to Grade ≤2 within 7 days, Grade ≥3 hyperglycemia or lipid profile results that occurred during non-fasting conditions, Grade 3 or 4 elevation of serum creatine phosphokinase levels or Grade 3 non clinically significant (as assessed by Investigator) laboratory abnormality that was asymptomatic; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count <500/microliter) lasting >5 days; Grade ≥4 thrombocytopenia lasting >48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting >72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.

    2. Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B [Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28]

      MTD was determined (by Investigator) based on the DLTs, as well as adverse events (AEs) in dose-escalation Stages 1, 1A, and 1B that did not meet protocol-defined DLT criteria but indicated intolerability of a given dose combination. Separate combination MTDs were determined for each dose-escalation stage. DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count <500/microliter) lasting >5 days; Grade ≥4 thrombocytopenia lasting >48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting >72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.

    3. Time of Maximum Concentration (Tmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3 [0-4 hours pre-cobimetinib (Pr-C) dose, 0.5, 2, 4, 6 hours post-cobimetinib (Po-C) dose on Day 3, Day 4]

    4. Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3 [0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4]

    5. Area Under the Concentration-Time Curve From Time 0 to 24 Hours Post-Dose (AUC0-24) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3 [0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4]

    6. Tmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3 [0-4 hours pre-pictilisib (Pr-P) dose, 0.5, 2, 4, 6 hours post-pictilisib (Po-P) dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3]

    7. Cmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3 [0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3]

    8. AUC0-24 of Pictilisib on Day 1 - Stage 1, Cohorts 1-3 [0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3]

    Secondary Outcome Measures

    1. Tmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14]

    2. Cmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14]

    3. AUC0-24 of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2]

    4. Tmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

    5. Cmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

    6. AUC0-24 of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

    7. Terminal Half-life (t1/2) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Half-life is the time measured for the plasma concentration to decrease by one half.

    8. Apparent Clearance (CL/F) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    9. Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2, 22]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).

    10. Tmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14]

    11. Cmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14]

    12. AUC0-24 of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2]

    13. Tmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

    14. Cmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

    15. AUC0-24 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

    16. t1/2 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    17. CL/F of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    18. Accumulation Ratio of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts [Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Day 2, 22]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).

    19. Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

    20. Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

    21. AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2]

    22. Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

    23. Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

    24. AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19]

    25. t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Half-life is the time measured for the plasma concentration to decrease by one half.

    26. CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    27. Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.

    28. Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

    29. Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

    30. AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2]

    31. Tmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

    32. Cmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

    33. AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19]

    34. t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    35. CL/F of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    36. Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.

    37. Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2]

    38. Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2]

    39. AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2]

    40. Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

    41. Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

    42. AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

    43. CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    44. Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

    45. Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2]

    46. Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2]

    47. AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2]

    48. Tmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

    49. Cmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

    50. AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

    51. CL/F of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

      Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    52. Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22]

      Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

    53. Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14]

      Stage 2 PK data were reported for each indication specific cohort separately.

    54. Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14]

      Stage 2 PK data were reported for each indication specific cohort separately.

    55. AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2 All Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2]

      Stage 2 PK data were reported for each indication specific cohort separately.

    56. Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately.

    57. Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately.

    58. AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

      Stage 2 PK data were reported for each indication specific cohort separately.

    59. t1/2 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22]

      Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

    60. CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    61. Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22]

      Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

    62. Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14]

      Stage 2 PK data were reported for each indication specific cohort separately.

    63. Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14]

      Stage 2 PK data were reported for each indication specific cohort separately.

    64. AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2]

      Stage 2 PK data were reported for each indication specific cohort separately.

    65. Tmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately.

    66. Cmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately.

    67. AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22]

      Stage 2 PK data were reported for each indication specific cohort separately.

    68. t1/2 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

    69. CL/F of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21]

      Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

    70. Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22]

      Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.

    71. Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

      Stage 2A PK data were reported for each indication specific cohort separately.

    72. Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

      Stage 2A PK data were reported for each indication specific cohort separately.

    73. AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2]

      Stage 2A PK data were reported for each indication specific cohort separately.

    74. Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as median.

    75. Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    76. AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    77. t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    78. CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    79. Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    80. Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

      Stage 2A PK data were reported for each indication specific cohort separately.

    81. Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17]

      Stage 2A PK data were reported for each indication specific cohort separately.

    82. AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2]

      Stage 2A PK data were reported for each indication specific cohort separately.

    83. Tmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    84. Cmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    85. AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    86. t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.

    87. CL/F of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    88. Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts [Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21]

      Stage 2A PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.

    89. Number of Participants With Best Overall Response - Dose Escalation Stages 1, 1A and 1B [Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)]

      Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) = disappearance of all target and non-target lesions. Partial Response (PR) = at least 30 percent (%) decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. Progressive disease (PD) = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment start.

    90. Duration of Objective Response - Dose Escalation Stages 1, 1A and 1B [Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)]

      Duration of objective response was defined as the time from first occurrence of a documented objective response (CR or PR) until the time of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). CR = disappearance of all target and non-target lesions. PR = at least 30 % decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.

    91. Progression-Free Survival (PFS) - Dose Escalation Stages 1, 1A and 1B [Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)]

      PFS was the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable

    • Evaluable disease or disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST)

    • Life expectancy greater than or equal to (>=) 12 weeks

    • Adequate hematologic and end organ function

    • Agreement to use an effective form of contraception for the duration of the study

    Exclusion Criteria:

    • History of prior significant toxicity from another mitogen-activated protein kinase (MEK) pathway inhibitor requiring discontinuation of treatment

    • History of prior significant toxicity from another phosphoinositide 3-kinase (PI3K) pathway inhibitor requiring discontinuation of treatment

    • Allergy or hypersensitivity to components of the cobimetinib or pictilisib formulations

    • Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment in Cycle 1

    • Experimental therapy within 4 weeks prior to first dose of study drug treatment in Cycle 1

    • Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose of study drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment

    • Prior anti-cancer therapy within 28 days before the first dose of study drug treatment in Cycle 1

    • History of diabetes requiring daily medication, or history of Grade >= 3 fasting hyperglycemia

    • Current severe, uncontrolled systemic disease

    • History of clinically significant cardiac or pulmonary dysfunction

    • History of malabsorption or other condition that would interfere with enteral absorption

    • Clinically significant history of liver disease (including cirrhosis), current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus

    • Any condition requiring anticoagulants, such as warfarin, heparin, or thrombolytics

    • Active autoimmune disease

    • Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment

    • Pregnancy, lactation, or breastfeeding

    • Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms

    • No other history of or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assays

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Baltimore Maryland United States 21231
    2 Boston Massachusetts United States 02114
    3 Boston Massachusetts United States 02215
    4 Detroit Michigan United States 48201
    5 Oklahoma City Oklahoma United States 73104
    6 Nashville Tennessee United States 37203

    Sponsors and Collaborators

    • Genentech, Inc.

    Investigators

    • Study Director: Iris Chan, M.D., Ph.D., Genentech, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT00996892
    Other Study ID Numbers:
    • MEK4752g
    • GO01330
    First Posted:
    Oct 16, 2009
    Last Update Posted:
    Dec 30, 2016
    Last Verified:
    Nov 1, 2016
    Keywords provided by Genentech, Inc.
    GDC0941
    GDC0973
    MEK
    MEK Inhibitor
    PI3K
    PI3K Inhibitor
    PI3 Kinase
    PI3 Kinase Inhibitor
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Study was terminated before initiation of Stage 2B; hence Stage 2B cohorts were not applicable.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S2A Expansion: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Stage 1 Cohort 1 (S1 C1): Participants received a single oral dose of pictilisib 80 milligrams (mg) capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 2 (S1 C2): Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 3 (S1 C3): Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 4 (S1 C4): Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 5 (S1 C5): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 6 (S1 C6): Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1 Cohort 6A (S1 C6A): Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort A (S1A CA): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort B (S1A CB): Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort C (S1A CC): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort D (S1A CD): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort E (S1A CE): Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort F (S1A CF): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1A Cohort G (S1A CG): Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1B Cohort AX (S1B CAX): Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1B Cohort BX (S1B CBX): Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1B Cohort CX (S1B CCX): Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 1B Cohort DX (S1B CDX): Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Stage 2 (S2) expansion cohort: Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR) T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; and KRAS mutant colorectal cancer (CRC). Stage 2A (S2A) expansion cohort: Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This indication specific cohort included participants with KRAS mutant NSCLC; EGFR T790M mutant and EGFR inhibitor-progressing NSCLC; pancreatic adenocarcinoma; KRAS mutant CRC, and KRAS mutant endometrioid carcinoma.
    Period Title: Dose-Escalation Stage 1
    STARTED 4 3 3 9 11 10 4 0 0 0 0 0 0 0 0 0 0 0 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 4 3 3 9 11 10 4 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Dose-Escalation Stage 1
    STARTED 0 0 0 0 0 0 0 3 3 4 7 9 8 5 0 0 0 0 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 3 3 4 7 9 8 5 0 0 0 0 0 0
    Period Title: Dose-Escalation Stage 1
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 3 3 5 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 3 3 5 0 0
    Period Title: Dose-Escalation Stage 1
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 35 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 35 0
    Period Title: Dose-Escalation Stage 1
    STARTED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 45
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 45

    Baseline Characteristics

    Arm/Group Title All Participants
    Arm/Group Description All participants who received cobimetinib and pictilisib in any dose combination until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Overall Participants 178
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56.6
    (12.0)
    Gender (Count of Participants)
    Female
    109
    61.2%
    Male
    69
    38.8%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B
    Description DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity, excluding the following: Grade 3 nausea, vomiting, or diarrhea that resolved to Grade ≤1 within 7 days, Grade 3 rash or Grade ≥3 fatigue that resolved to Grade ≤2 within 7 days, Grade ≥3 hyperglycemia or lipid profile results that occurred during non-fasting conditions, Grade 3 or 4 elevation of serum creatine phosphokinase levels or Grade 3 non clinically significant (as assessed by Investigator) laboratory abnormality that was asymptomatic; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count <500/microliter) lasting >5 days; Grade ≥4 thrombocytopenia lasting >48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting >72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.
    Time Frame Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

    Outcome Measure Data

    Analysis Population Description
    Safety-evaluable population included all participants who received at least one dose of study drug. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 9 11 10 4 3 3 4 7 9 8 5 4 3 3 5
    Number [participants]
    0
    0%
    0
    NaN
    0
    NaN
    1
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    2
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    2. Primary Outcome
    Title Maximum Tolerated Combination Doses of Cobimetinib and Pictilisib During Dose-Escalation Stages 1, 1A and 1B
    Description MTD was determined (by Investigator) based on the DLTs, as well as adverse events (AEs) in dose-escalation Stages 1, 1A, and 1B that did not meet protocol-defined DLT criteria but indicated intolerability of a given dose combination. Separate combination MTDs were determined for each dose-escalation stage. DLT was defined as 1 of the following toxicities considered treatment related by Investigator: Grade ≥3 non-hematologic, non-hepatic organ toxicity; Grade ≥3 febrile neutropenia; Grade ≥4 neutropenia (absolute neutrophil count <500/microliter) lasting >5 days; Grade ≥4 thrombocytopenia lasting >48 hours; Grade ≥4 anemia; Grade ≥3 total bilirubin, hepatic transaminase, alkaline phosphatase, lasting >72 hours; Grade ≥2 diffusion capacity of the lung for carbon monoxide concomitant with an absolute decrease of ≥20 percentage points from baseline.
    Time Frame Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28

    Outcome Measure Data

    Analysis Population Description
    Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome and n = participants evaluable for specified categories.
    Arm/Group Title All Participants - Stages 1, 1A, 1B
    Arm/Group Description All participants who received cobimetinib and pictilisib in any dose combination during Stages 1, 1A, and 1B, until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 98
    Stage 1: Cobimetinib (n = 44)
    40
    Stage 1: Pictilisib (n = 44)
    100
    Stage 1A: Cobimetinib (n = 34)
    125
    Stage 1A: Pictilisib (n = 34)
    180
    Stage 1B: Cobimetinib (n = 20)
    NA
    Stage 1B: Pictilisib (n = 20)
    NA
    3. Primary Outcome
    Title Time of Maximum Concentration (Tmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours pre-cobimetinib (Pr-C) dose, 0.5, 2, 4, 6 hours post-cobimetinib (Po-C) dose on Day 3, Day 4

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) population included all participants who had at least one cobimetinib and pictilisib plasma concentration available. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Median (Full Range) [hours]
    4.00
    4.00
    2.00
    4. Primary Outcome
    Title Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)]
    27.6
    (95)
    16.6
    (78)
    97.0
    (63)
    5. Primary Outcome
    Title Area Under the Concentration-Time Curve From Time 0 to 24 Hours Post-Dose (AUC0-24) of Cobimetinib on Day 3 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Day 3, Day 4

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Geometric Mean (Geometric Coefficient of Variation) [nonograms*hour per milliliter (ng*h/mL)]
    392
    (88)
    279
    (75)
    1190
    (53)
    6. Primary Outcome
    Title Tmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours pre-pictilisib (Pr-P) dose, 0.5, 2, 4, 6 hours post-pictilisib (Po-P) dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Median (Full Range) [hours]
    3.00
    4.00
    2.00
    7. Primary Outcome
    Title Cmax of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    162
    (37)
    185
    (27)
    280
    (41)
    8. Primary Outcome
    Title AUC0-24 of Pictilisib on Day 1 - Stage 1, Cohorts 1-3
    Description
    Time Frame 0-4 hours Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Day 1, Day 2, 0-4 hours Pr-C dose on Day 3

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    1680
    (16)
    1950
    (50)
    2680
    (83)
    9. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Median (Full Range) [hours]
    4.00
    4.00
    2.00
    2.00
    2.00
    4.00
    3.00
    10. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    20.2
    (100)
    17.7
    (62)
    87.4
    (73)
    101
    (63)
    61.0
    (45)
    131
    (66)
    138
    (61)
    11. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 8, Cycle 1 Days 9; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    299
    (62)
    311
    (53)
    1320
    (56.6)
    1300
    (61)
    957
    (42)
    2050
    (71)
    1790
    (56)
    12. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Median (Full Range) [hours]
    6.00
    4.00
    2.00
    2.00
    4.00
    3.0
    4
    13. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    37.1
    (5.6)
    52.2
    (57)
    228
    (120)
    167
    (56)
    138
    (63)
    245
    (79)
    87.4
    (NA)
    14. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    749
    (1.4)
    900
    (70)
    4130
    (94)
    2410
    (66)
    2460
    (57)
    4050
    (110)
    1120
    (NA)
    15. Secondary Outcome
    Title Terminal Half-life (t1/2) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Half-life is the time measured for the plasma concentration to decrease by one half.
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Geometric Mean (Full Range) [hours]
    49.3
    37.9
    31.7
    34.1
    43.2
    45.7
    40.5
    16. Secondary Outcome
    Title Apparent Clearance (CL/F) of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Geometric Mean (Geometric Coefficient of Variation) [Liters per hour (L/hr)]
    26.7
    (1.4)
    22.2
    (70)
    9.67
    (94)
    16.6
    (66)
    16.2
    (61)
    14.8
    (110)
    53.6
    (NA)
    17. Secondary Outcome
    Title Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).
    Time Frame Cohorts 1-3: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2, 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 9 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    2.51
    (63)
    2.89
    (43)
    3.14
    (73)
    2.03
    (36)
    2.90
    (73)
    2.83
    (54)
    1.77
    (NA)
    18. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    2.00
    2.00
    2.00
    19. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    196
    (20)
    193
    (16)
    329
    (26)
    390
    (60)
    302
    (34)
    272
    (54)
    355
    (83)
    20. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 8, Cycle 1 Day 9; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 8 11 10 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    1660
    (28)
    2150
    (43)
    2600
    (28)
    3360
    (43)
    2770
    (43)
    2870
    (48)
    3240
    (68)
    21. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 8 3 1
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    2.00
    2.00
    2.00
    22. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 8 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    198
    (38)
    278
    (100)
    459
    (20)
    409
    (49)
    374
    (69)
    396
    (48)
    441
    (NA)
    23. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 8 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    2500
    (21)
    2930
    (150)
    5500
    (34)
    3890
    (63)
    4320
    (58)
    4510
    (40)
    4070
    (NA)
    24. Secondary Outcome
    Title t1/2 of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 0 0 2 8 3 0
    Geometric Mean (Full Range) [hours]
    25.8
    NA
    24.7
    27.7
    25. Secondary Outcome
    Title CL/F of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 28, Cycle 1 Day 29, Cycle 2 Days 1, 15, 21; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 8 3 1
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    32.0
    (21)
    34.1
    (150)
    14.5
    (34)
    25.7
    (63)
    30.1
    (58)
    22.2
    (40)
    24.6
    (NA)
    26. Secondary Outcome
    Title Accumulation Ratio of Pictilisib on Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) - Stage 1 All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 (Cycle 1 Day 28 for Cohorts 1-3) divided by AUC0-24 at Cycle 1 Day 1 (Cycle 1 Day 8 for Cohorts 1-3).
    Time Frame Cohorts 1-3: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 8 and 28, Cycle 1 Days 9, 29; Cohorts 4-6A: Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Day 2, 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 5 8 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    1.51
    (47)
    1.36
    (79)
    2.11
    (6.0)
    1.16
    (34)
    1.71
    (29)
    1.70
    (25)
    2.8
    (NA)
    27. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Median (Full Range) [hours]
    2.00
    4.00
    2.00
    4.00
    4.00
    5.00
    4.00
    28. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    301
    (87)
    137
    (66)
    436
    (67)
    184
    (47)
    275
    (72)
    333
    (45)
    311
    (48)
    29. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    4950
    (80)
    2320
    (61)
    5520
    (59)
    2620
    (50)
    4250
    (75)
    5100
    (47)
    5090
    (45)
    30. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    4.00
    4.00
    5.00
    3.00
    31. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    802
    (24)
    372
    (45)
    616
    (39)
    204
    (57)
    409
    (43)
    475
    (86)
    682
    (23)
    32. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    13400
    (18)
    5680
    (55)
    9990
    (28)
    3060
    (50)
    6980
    (55)
    7740
    (69)
    11100
    (23)
    33. Secondary Outcome
    Title t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Half-life is the time measured for the plasma concentration to decrease by one half.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 2 3 3 6 6 2 4
    Geometric Mean (Full Range) [hours]
    NA
    46.1
    47.4
    48.8
    48
    NA
    46.2
    34. Secondary Outcome
    Title CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    7.49
    (18)
    17.6
    (55)
    12.5
    (28)
    40.9
    (50)
    17.9
    (55)
    19.4
    (69)
    13.6
    (23)
    35. Secondary Outcome
    Title Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    2.70
    (57)
    2.44
    (60)
    1.46
    (30)
    1.11
    (67)
    1.52
    (120)
    1.75
    (40)
    1.84
    (8.1)
    36. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    2.00
    2.00
    4.00
    37. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    547
    (80)
    408
    (190)
    390
    (76)
    367
    (61)
    832
    (35)
    619
    (110)
    514
    (81)
    38. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 4 7 9 8 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    6900
    (62)
    4900
    (170)
    3670
    (72)
    4280
    (48)
    8440
    (32)
    5650
    (88)
    6680
    (53)
    39. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    3.00
    2.00
    3.00
    40. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    809
    (41)
    709
    (71)
    597
    (38)
    579
    (100)
    833
    (49)
    743
    (53)
    646
    (24)
    41. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    11300
    (21)
    7680
    (88)
    6990
    (38)
    6120
    (110)
    12100
    (58)
    8140
    (58)
    10100
    (44)
    42. Secondary Outcome
    Title t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 2 2 3 1 6 2 2
    Geometric Mean (Full Range) [hours]
    NA
    NA
    34.9
    36.5
    38.4
    NA
    NA
    43. Secondary Outcome
    Title CL/F of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    11.5
    (21)
    23.5
    (88)
    18.6
    (38)
    29.4
    (110)
    20.3
    (58)
    22.1
    (58)
    24.2
    (44)
    44. Secondary Outcome
    Title Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 1A All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 18 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 18, Cycle 1 Days 2, 19

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 3 3 3 6 6 6 4
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    1.64
    (40)
    1.57
    (45)
    1.89
    (110)
    1.15
    (55)
    1.56
    (42)
    1.60
    (100)
    1.46
    (100)
    45. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 5
    Median (Full Range) [hours]
    3.00
    2.00
    4.00
    4.00
    46. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    55
    (160)
    123
    (56)
    45.6
    (110)
    77.8
    (110)
    47. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 1
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    855
    (150)
    1750
    (77)
    699
    (72)
    2460
    (NA)
    48. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 4
    Median (Full Range) [hours]
    5.00
    4.00
    2.00
    6.00
    49. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    174
    (50)
    232
    (120)
    158
    (73)
    245
    (45)
    50. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    3270
    (64)
    4320
    (150)
    NA
    (NA)
    4190
    (52)
    51. Secondary Outcome
    Title CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 4
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    12.2
    (64)
    9.26
    (150)
    NA
    (NA)
    14.3
    (52)
    52. Secondary Outcome
    Title Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 1
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    3.82
    (60)
    2.46
    (46)
    NA
    (NA)
    1.15
    (57)
    53. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 5
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    4.00
    54. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 5
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    527
    (67)
    609
    (27)
    168
    (130)
    363
    (64)
    55. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Day 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 5
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    5380
    (50)
    6540
    (20)
    2260
    (70)
    4160
    (77)
    56. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 4
    Median (Full Range) [hours]
    4.00
    2.00
    4.00
    5.00
    57. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 3 4
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    508
    (10)
    1010
    (27)
    227
    (19)
    408
    (62)
    58. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 4
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    7000
    (12)
    13500
    (39)
    NA
    (NA)
    5410
    (57)
    59. Secondary Outcome
    Title CL/F of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 4
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    18.6
    (12)
    13.3
    (39)
    NA
    (NA)
    33.3
    (57)
    60. Secondary Outcome
    Title Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 1B All Cohorts
    Description Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 3 2 4
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    1.30
    (40)
    2.06
    (19)
    NA
    (NA)
    1.36
    (57)
    61. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Median (Full Range) [hours]
    2.00
    4.00
    3.00
    4.00
    62. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    73.8
    (38)
    90.7
    (87)
    116
    (63)
    48.2
    (97)
    63. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2 All Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    1080
    (26)
    1330
    (100)
    1790
    (73)
    700
    (84)
    64. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Median (Full Range) [hours]
    4.00
    4.00
    2.00
    NA
    65. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    119
    (62)
    237
    (63)
    254
    (120)
    NA
    (NA)
    66. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    2200
    (57)
    4570
    (68)
    4700
    (120)
    NA
    (NA)
    67. Secondary Outcome
    Title t1/2 of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Geometric Mean (Full Range) [hours]
    42.5
    51.5
    36.0
    NA
    68. Secondary Outcome
    Title CL/F of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    18.2
    (57)
    8.76
    (68)
    8.52
    (120)
    NA
    (NA)
    69. Secondary Outcome
    Title Accumulation Ratio of Cobimetinib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    1.92
    (51)
    3.28
    (52)
    2.60
    (63)
    NA
    (NA)
    70. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    4.00
    71. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 14

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    298
    (52)
    355
    (55)
    315
    (58)
    253
    (90)
    72. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 7 9 12 6
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    3010
    (37)
    3800
    (63)
    3210
    (59)
    3340
    (78)
    73. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 8 10 2
    Median (Full Range) [hours]
    4.00
    2.00
    2.00
    NA
    74. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 8 10 2
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    231
    (63)
    362
    (60)
    369
    (66)
    NA
    (NA)
    75. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 8 10 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    3390
    (39)
    5250
    (66)
    4580
    (56)
    NA
    (NA)
    76. Secondary Outcome
    Title t1/2 of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 10 1
    Geometric Mean (Full Range) [hours]
    183
    28.5
    26.6
    30.9
    77. Secondary Outcome
    Title CL/F of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 21, Cycle 1 Day 22, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 8 10 2
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    29.5
    (39)
    19.1
    (66)
    21.8
    (56)
    NA
    (NA)
    78. Secondary Outcome
    Title Accumulation Ratio of Pictilisib on Cycle 1 Day 21 - Stage 2 Individual Indication Specific Cohorts
    Description Stage 2 PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Days 1 and 21, Cycle 1 Days 2 and 22

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2 EGFR T790M NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS NSCLC: 40 mg Cobimetinib + 100 mg Pictilisib S2 KRAS CRC: 40 mg Cobimetinib + 100 mg Pictilisib S2 Pancreatic: 40 mg Cobimetinib + 100 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 4 8 10 2
    Geometric Mean (Geometric Coefficient of Variation) [ratio]
    0.90
    (40)
    1.39
    (58)
    1.43
    (57)
    NA
    (NA)
    79. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Median (Full Range) [hours]
    4.00
    6.00
    4.00
    4.00
    2.00
    80. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    487
    (NA)
    334
    (44)
    256
    (130)
    277
    (110)
    408
    (89)
    81. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    6560
    (NA)
    5210
    (43)
    4470
    (120)
    4090
    (120)
    5630
    (90)
    82. Secondary Outcome
    Title Tmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as median.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Median (Full Range) [hours]
    4.00
    4.00
    3.00
    4.00
    NA
    83. Secondary Outcome
    Title Cmax of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    587
    (NA)
    502
    (16)
    469
    (40)
    393
    (44)
    NA
    (NA)
    84. Secondary Outcome
    Title AUC0-24 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    9560
    (NA)
    7920
    (16)
    7390
    (32)
    5790
    (46)
    NA
    (NA)
    85. Secondary Outcome
    Title t1/2 of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Full Range) [hours]
    37.7
    38.6
    50.2
    42.6
    NA
    86. Secondary Outcome
    Title CL/F of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    13.1
    (NA)
    15.8
    (16)
    16.9
    (32)
    21.6
    (46)
    NA
    (NA)
    87. Secondary Outcome
    Title Accumulation Ratio of Cobimetinib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-C dose, 0.5, 2, 4, 6 hours Po-C dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    1.46
    (NA)
    1.43
    (51)
    1.89
    (94)
    1.72
    (83)
    NA
    (NA)
    88. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    4.00
    89. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2, 8, 15-17

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    714
    (NA)
    265
    (140)
    289
    (100)
    393
    (90)
    369
    (35)
    90. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 1 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 1, Cycle 1 Days 2

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 8 12 12 3
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    8050
    (NA)
    3380
    (100)
    3310
    (76)
    4030
    (88)
    4500
    (16)
    91. Secondary Outcome
    Title Tmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Median (Full Range) [hours]
    2.00
    2.00
    2.00
    2.00
    NA
    92. Secondary Outcome
    Title Cmax of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    412
    (NA)
    518
    (67)
    520
    (84)
    334
    (83)
    NA
    (NA)
    93. Secondary Outcome
    Title AUC0-24 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    6300
    (NA)
    6310
    (31)
    5930
    (73)
    3990
    (74)
    NA
    (NA)
    94. Secondary Outcome
    Title t1/2 of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Half-life is the time measured for the plasma concentration to decrease by one half.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 0 5 8 9 1
    Geometric Mean (Full Range) [hours]
    44.6
    58.2
    37.8
    30.3
    95. Secondary Outcome
    Title CL/F of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [L/hr]
    28.6
    (NA)
    28.5
    (31)
    30.3
    (73)
    45.1
    (74)
    NA
    (NA)
    96. Secondary Outcome
    Title Accumulation Ratio of Pictilisib on Cycle 1 Day 18 - Stage 2A Individual Indication Specific Cohorts
    Description Stage 2A PK data were reported for each indication specific cohort separately. Accumulation ratio was calculated as: AUC0-24 at Cycle 1 Day 21 divided by AUC0-24 at Cycle 1 Day 1. As planned, summary statistics were not derived if fewer than 3 participants had available data; however, if the number of participants analyzed = 1, then the observed data of the single participant was reported as geometric mean.
    Time Frame Pr-P dose, 0.5, 2, 4, 6 hours Po-P dose on Cycle 1 Day 18, Cycle 1 Day 19, Cycle 2 Days 1, 15, 21

    Outcome Measure Data

    Analysis Population Description
    PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S2A EGFR T790M NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS NSCLC: 125 mg Cobimetinib + 180 mg Pictilisib S2A KRAS CRC: 125 mg Cobimetinib + 180 mg Pictilisib S2A Pancreatic: 125 mg Cobimetinib + 180 mg Pictilisib S2A Endometrioid: 125 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants with EGFR T790M mutant and EGFR inhibitor-progressing NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS NSCLC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS CRC received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with pancreatic adenocarcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants with KRAS mutant endometrioid carcinoma received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 1 5 8 9 2
    Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
    0.78
    (NA)
    1.61
    (110)
    1.90
    (50)
    1.03
    (84)
    NA
    (NA)
    97. Secondary Outcome
    Title Number of Participants With Best Overall Response - Dose Escalation Stages 1, 1A and 1B
    Description Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) = disappearance of all target and non-target lesions. Partial Response (PR) = at least 30 percent (%) decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. Progressive disease (PD) = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment start.
    Time Frame Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)

    Outcome Measure Data

    Analysis Population Description
    Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants from S1 C4 as well as S2 expansion cohort. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants form S1A CD as well as S2A expansion cohort. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 2 3 3 31 10 8 1 2 3 4 35 7 6 3 4 3 3 3
    PR
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    2
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    SD
    2
    1.1%
    2
    NaN
    1
    NaN
    15
    NaN
    5
    NaN
    3
    NaN
    1
    NaN
    0
    NaN
    2
    NaN
    3
    NaN
    16
    NaN
    5
    NaN
    2
    NaN
    0
    NaN
    1
    NaN
    1
    NaN
    0
    NaN
    1
    NaN
    PD
    0
    0%
    1
    NaN
    2
    NaN
    16
    NaN
    5
    NaN
    4
    NaN
    0
    NaN
    2
    NaN
    1
    NaN
    0
    NaN
    17
    NaN
    1
    NaN
    4
    NaN
    3
    NaN
    3
    NaN
    2
    NaN
    3
    NaN
    2
    NaN
    Unable to Evaluate
    0
    0%
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    98. Secondary Outcome
    Title Duration of Objective Response - Dose Escalation Stages 1, 1A and 1B
    Description Duration of objective response was defined as the time from first occurrence of a documented objective response (CR or PR) until the time of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). CR = disappearance of all target and non-target lesions. PR = at least 30 % decrease in sum of the longest diameter of measured lesions taking as reference the baseline sum of the longest diameter. PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.
    Time Frame Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)

    Outcome Measure Data

    Analysis Population Description
    Data for this outcome measure was not collected as per changes in planned analysis.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants from S1 C4 as well as S2 expansion cohort. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants form S1A CD as well as S2A expansion cohort. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
    99. Secondary Outcome
    Title Progression-Free Survival (PFS) - Dose Escalation Stages 1, 1A and 1B
    Description PFS was the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST, or death from any cause during the study (within 30 days after the last dose of study treatment). PD = at least 20% increase in the sum of the longest diameter of measured lesions taking as reference the smallest sum of the longest diameter since treatment start or appearance of one or more new lesions.
    Time Frame Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)

    Outcome Measure Data

    Analysis Population Description
    Data for this outcome measure was not collected as per changes in planned analysis.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants from S1 C4 as well as S2 expansion cohort. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants form S1A CD as well as S2A expansion cohort. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

    Adverse Events

    Time Frame Up to 30 days after last dose (last dose = up to Cycle 15, cycle length = 28 days)
    Adverse Event Reporting Description Safety evaluable population.
    Arm/Group Title S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Arm/Group Description Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 100 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 20 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received a single oral dose of pictilisib 80 mg capsules on Day 1 of Cycle 1 and a single oral dose of cobimetinib 40 mg capsules on Day 3 of Cycle 1, followed by continuous 21-day dosing with both cobimetinib and pictilisib at same doses from Days 8 to 28 and then 7 days off study drugs from Days 29 to 35 (Cycle 1 = 35 days). In subsequent cycles (28-day cycles), participants received 21-day dosing with both cobimetinib and pictilisib at same doses from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants from S1 C4 as well as S2 expansion cohort. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 80 mg capsules and pictilisib 100 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 100 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 130 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. This arm included participants form S1A CD as well as S2A expansion cohort. Participants received cobimetinib 125 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 180 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 150 mg capsules on Days 1, 4, 8, 11, 15, and 18 and pictilisib 245 mg capsules from Days 1 to 21 and then 7 days off study drugs from Days 22 to 28 in continuous 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 40 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 130 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Participants received cobimetinib 60 mg capsules and pictilisib 180 mg capsules from Days 1 to 7 and then from Days 15 to 21 in continuous 28-day cycles. Participants were off study drugs from Days 8 to 14 and from Days 22 to 28. Treatment continued until disease progression, unacceptable toxicity, or any other discontinuation criterion was met.
    All Cause Mortality
    S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/4 (50%) 0/3 (0%) 1/3 (33.3%) 25/43 (58.1%) 6/11 (54.5%) 6/10 (60%) 2/4 (50%) 2/3 (66.7%) 2/3 (66.7%) 3/4 (75%) 28/52 (53.8%) 4/9 (44.4%) 5/8 (62.5%) 3/5 (60%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/5 (40%)
    Blood and lymphatic system disorders
    Febrile neutropenia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cardiac disorders
    Atrial fibrillation 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cardiac arrest 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Stress cardiomyopathy 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Eye disorders
    Diplopia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Gastrointestinal disorders
    Diarrhoea 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 4/10 (40%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 3/52 (5.8%) 0/9 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Small intestinal obstruction 0/4 (0%) 0/3 (0%) 0/3 (0%) 4/43 (9.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vomiting 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nausea 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Abdominal pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Stomatitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Colititis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Abdominal distension 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Duodenal ulcer 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dyspepsia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Ileus 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Upper gastrointestinal haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    General disorders
    Pyrexia 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Fatigue 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Asthenia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Device occlusion 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Face oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oedema peripheral 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hepatobiliary disorders
    Bile duct obstruction 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Immune system disorders
    Hypersensitivity 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Anaphylactic reaction 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Infections and infestations
    Pneumonia 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Bacteraemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Sepsis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Clostridium difficile colitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Escherichia bacteraemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Ercherichia sepsis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lung infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Perirectal abscess 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urosepsis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vaginal infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urinary tract infection 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Injury, poisoning and procedural complications
    Wound dehiscence 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Investigations
    Blood creatine phosphokinase increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood bilirubin increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Carbon monoxide diffusing capacity decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dehydration 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Failure to thrive 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Musculoskeletal and connective tissue disorders
    Fistula 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    colorectal cancer 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Malignant neoplasm progression 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Adenocarcinoma 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cervix carcinoma 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Colon cancer metastatic 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Endometrial cancer 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Gastrooesophageal cancer 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lung adenocarcinoma metastatic 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lung neoplasm malignant 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Malignant ascites 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Metastasis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Metastatic malignant melanoma 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Rectal cancer metastatic 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nervous system disorders
    Cerebrovascular accident 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Embolic stroke 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Partial seizures 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Renal and urinary disorders
    Renal failure acute 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urinary retention 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Reproductive system and breast disorders
    Pelvic pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dyspnoea 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypoxia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pleural effusion 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pneumonitits 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Respiratory failure 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haemoptysis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Skin and subcutaneous tissue disorders
    Rash 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vascular disorders
    Hypotension 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Other (Not Including Serious) Adverse Events
    S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib S1 C4/S2 Expansion: 40 mg Cobimetinib + 100 mg Pictilisib S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib S1 C6A: 80 mg Cobimetinib + 100 mg Pictilisib S1A CA: 100 mg Cobimetinib + 130 mg Pictilisib S1A CB: 100 mg Cobimetinib + 180 mg Pictilisib S1A CC: 125 mg Cobimetinib + 130 mg Pictilisib S1A CD/S2A Expension: 125 mg Cobimetinib + 180 mg Pictilisib S1A CE: 125 mg Cobimetinib + 245 mg Pictilisib S1A CF: 150 mg Cobimetinib + 180 mg Pictilisib S1A CG: 150 mg Cobimetinib + 245 mg Pictilisib S1B CAX: 40 mg Cobimetinib + 130 mg Pictilisib S1B CBX: 40 mg Cobimetinib + 180 mg Pictilisib S1B CCX: 60 mg Cobimetinib + 130 mg Pictilisib S1B CDX: 60 mg Cobimetinib + 180 mg Pictilisib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/4 (100%) 3/3 (100%) 3/3 (100%) 42/43 (97.7%) 11/11 (100%) 10/10 (100%) 4/4 (100%) 3/3 (100%) 3/3 (100%) 4/4 (100%) 52/52 (100%) 9/9 (100%) 8/8 (100%) 5/5 (100%) 4/4 (100%) 3/3 (100%) 3/3 (100%) 5/5 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 5/43 (11.6%) 0/11 (0%) 3/10 (30%) 0/4 (0%) 2/3 (66.7%) 1/3 (33.3%) 0/4 (0%) 7/52 (13.5%) 1/9 (11.1%) 1/8 (12.5%) 0/5 (0%) 2/4 (50%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Coagulopathy 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Eosinophilia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Leukopenia 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lymphopenia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 2/3 (66.7%) 0/3 (0%) 0/5 (0%)
    Neutropenia 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Thrombocytopenia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 3/43 (7%) 0/11 (0%) 2/10 (20%) 1/4 (25%) 0/3 (0%) 2/3 (66.7%) 1/4 (25%) 3/52 (5.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Cardiac disorders
    Palpitations 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pericardial effusion 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Sinus tachycardia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Tachycardia 1/4 (25%) 0/3 (0%) 0/3 (0%) 6/43 (14%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Ear and labyrinth disorders
    Ear discomfort 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Ear pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Hypoacusis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Motion sickness 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Endocrine disorders
    Hyperthyroidism 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Eye disorders
    Asthenopia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cataract 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Eye Pruritus 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lacrimation increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Periorbital oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 4/43 (9.3%) 0/11 (0%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/5 (20%)
    Photophobia 1/4 (25%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Retinal tear 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vision Blurred 1/4 (25%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/5 (20%)
    Visual impairment 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vitreous floaters 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Gastrointestinal disorders
    Abdominal discomfort 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 3/43 (7%) 2/11 (18.2%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Abdominal distension 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 5/43 (11.6%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 2/5 (40%)
    Abdominal pain 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 7/43 (16.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 13/52 (25%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 1/4 (25%) 2/3 (66.7%) 0/3 (0%) 0/5 (0%)
    Abdominal pain lower 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Abdominal pain upper 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 4/43 (9.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cheilitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Colitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Constipation 2/4 (50%) 0/3 (0%) 1/3 (33.3%) 16/43 (37.2%) 2/11 (18.2%) 1/10 (10%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 16/52 (30.8%) 3/9 (33.3%) 2/8 (25%) 0/5 (0%) 0/4 (0%) 2/3 (66.7%) 1/3 (33.3%) 0/5 (0%)
    Diarrhoea 3/4 (75%) 3/3 (100%) 3/3 (100%) 39/43 (90.7%) 9/11 (81.8%) 8/10 (80%) 4/4 (100%) 2/3 (66.7%) 3/3 (100%) 4/4 (100%) 44/52 (84.6%) 8/9 (88.9%) 7/8 (87.5%) 4/5 (80%) 3/4 (75%) 2/3 (66.7%) 3/3 (100%) 3/5 (60%)
    Dry mouth 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 6/43 (14%) 2/11 (18.2%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 2/3 (66.7%) 1/4 (25%) 5/52 (9.6%) 0/9 (0%) 2/8 (25%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 2/5 (40%)
    Duodenal ulcer haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dyspepsia 1/4 (25%) 0/3 (0%) 0/3 (0%) 8/43 (18.6%) 0/11 (0%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/4 (50%) 13/52 (25%) 0/9 (0%) 2/8 (25%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 2/5 (40%)
    Dysphagia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Faecal incontinence 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Faeces discoloured 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Flatulence 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/5 (40%)
    Gastritis 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Gastrooesophageal reflux disease 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 5/43 (11.6%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 4/52 (7.7%) 2/9 (22.2%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Gingival pain 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Glossodynia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haematochezia 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haemorrhoids 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypoaesthesia oral 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lip dry 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lip oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Lip pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Nausea 3/4 (75%) 2/3 (66.7%) 3/3 (100%) 25/43 (58.1%) 6/11 (54.5%) 6/10 (60%) 3/4 (75%) 1/3 (33.3%) 3/3 (100%) 3/4 (75%) 36/52 (69.2%) 7/9 (77.8%) 7/8 (87.5%) 3/5 (60%) 1/4 (25%) 2/3 (66.7%) 1/3 (33.3%) 5/5 (100%)
    Obstruction gastric 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Odynophagia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oesophagitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oral mucosal erythema 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oral pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pancreatitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Proctalgia 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Rectal haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Retching 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Stomatitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 11/43 (25.6%) 1/11 (9.1%) 3/10 (30%) 2/4 (50%) 1/3 (33.3%) 3/3 (100%) 2/4 (50%) 12/52 (23.1%) 4/9 (44.4%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/5 (20%)
    Swollen tongue 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Vomiting 3/4 (75%) 0/3 (0%) 2/3 (66.7%) 27/43 (62.8%) 5/11 (45.5%) 8/10 (80%) 3/4 (75%) 2/3 (66.7%) 0/3 (0%) 4/4 (100%) 32/52 (61.5%) 5/9 (55.6%) 6/8 (75%) 3/5 (60%) 0/4 (0%) 3/3 (100%) 1/3 (33.3%) 4/5 (80%)
    General disorders
    Asthenia 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 5/52 (9.6%) 1/9 (11.1%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Catheter site pruritus 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Catheter site rash 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Chest discomfort 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Chest pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Chills 1/4 (25%) 0/3 (0%) 2/3 (66.7%) 3/43 (7%) 1/11 (9.1%) 1/10 (10%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 6/52 (11.5%) 3/9 (33.3%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Early satiety 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 2/9 (22.2%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Face oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Fatigue 3/4 (75%) 1/3 (33.3%) 1/3 (33.3%) 26/43 (60.5%) 5/11 (45.5%) 5/10 (50%) 3/4 (75%) 1/3 (33.3%) 2/3 (66.7%) 2/4 (50%) 29/52 (55.8%) 6/9 (66.7%) 7/8 (87.5%) 3/5 (60%) 3/4 (75%) 1/3 (33.3%) 2/3 (66.7%) 2/5 (40%)
    Generalised oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Influenza like illness 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Local swelling 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Localized oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Malaise 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 2/11 (18.2%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Oedema peripheral 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 7/43 (16.3%) 4/11 (36.4%) 2/10 (20%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/4 (50%) 8/52 (15.4%) 2/9 (22.2%) 0/8 (0%) 2/5 (40%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pyrexia 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 11/43 (25.6%) 4/11 (36.4%) 3/10 (30%) 1/4 (25%) 1/3 (33.3%) 1/3 (33.3%) 2/4 (50%) 16/52 (30.8%) 3/9 (33.3%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/5 (20%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Immune system disorders
    Hypersensitivity 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Seasonal allergy 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Infections and infestations
    Bronchitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Candida infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cellulitits 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Cystitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Fungal skin infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Herpes zoster 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lip infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Liver abscess 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lung infection 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nasopharyngitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oral candidiasis 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Paronychia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Penile infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pneumonia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 2/9 (22.2%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Rhinitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Sepsis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Sinusitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Upper respiratory tract infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 4/43 (9.3%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 2/4 (50%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Urinary tract infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 5/43 (11.6%) 1/11 (9.1%) 1/10 (10%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 3/52 (5.8%) 2/9 (22.2%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Viral infection 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Injury, poisoning and procedural complications
    Arterial injury 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Contusion 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Excoriation 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Fall 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Incision site rash 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Procedural pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Investigations
    Alanine aminotransferase increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Amylase increased 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Aspartate aminotransferase increased 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 4/43 (9.3%) 2/11 (18.2%) 4/10 (40%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 3/52 (5.8%) 1/9 (11.1%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%) 1/3 (33.3%) 1/3 (33.3%) 0/5 (0%)
    Bilirubin conjugated increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood alkaline phosphatase increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 5/43 (11.6%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 2/8 (25%) 0/5 (0%) 3/4 (75%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Blood bilirubin increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 1/3 (33.3%) 2/3 (66.7%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood calcium decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood chloride decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood chloride increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood creatine phosphokinase increased 1/4 (25%) 2/3 (66.7%) 0/3 (0%) 5/43 (11.6%) 3/11 (27.3%) 3/10 (30%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 6/52 (11.5%) 2/9 (22.2%) 2/8 (25%) 2/5 (40%) 2/4 (50%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood creatine phosphokinase mb increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood creatinine increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 2/10 (20%) 1/4 (25%) 2/3 (66.7%) 0/3 (0%) 1/4 (25%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Blood glucose increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood iron decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood lactate dehydrogenase increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 2/4 (50%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood urea increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blood uric acid increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Carbon dioxide decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haermatocrit decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haemoglobin decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Heart rate increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Lipase increased 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Neutrophil count decreased 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Platelet count decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Platelet count increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Troponin increased 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Weight decreased 0/4 (0%) 0/3 (0%) 0/3 (0%) 9/43 (20.9%) 1/11 (9.1%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 6/52 (11.5%) 2/9 (22.2%) 3/8 (37.5%) 2/5 (40%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    White blood cell count decreased 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 2/4 (50%) 0/3 (0%) 1/3 (33.3%) 16/43 (37.2%) 3/11 (27.3%) 5/10 (50%) 1/4 (25%) 1/3 (33.3%) 3/3 (100%) 4/4 (100%) 21/52 (40.4%) 3/9 (33.3%) 5/8 (62.5%) 2/5 (40%) 2/4 (50%) 1/3 (33.3%) 1/3 (33.3%) 2/5 (40%)
    Dehydration 0/4 (0%) 0/3 (0%) 2/3 (66.7%) 8/43 (18.6%) 2/11 (18.2%) 5/10 (50%) 2/4 (50%) 1/3 (33.3%) 1/3 (33.3%) 0/4 (0%) 9/52 (17.3%) 1/9 (11.1%) 2/8 (25%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Hypercholesterolaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hyperglycaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hyperkalaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypernatraemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypertriglyceridaemia 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hyperuricaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypoalbuminaemia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 5/43 (11.6%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 3/4 (75%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypocalcaemia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypokalaemia 0/4 (0%) 0/3 (0%) 2/3 (66.7%) 9/43 (20.9%) 2/11 (18.2%) 2/10 (20%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 10/52 (19.2%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Hypomagnesaemia 1/4 (25%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 1/11 (9.1%) 4/10 (40%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 5/52 (9.6%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hyponatraemia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 5/43 (11.6%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 2/9 (22.2%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypophagia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypophosphataemia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 2/43 (4.7%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 2/5 (40%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Iron deficiency 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/4 (0%) 0/3 (0%) 0/3 (0%) 5/43 (11.6%) 2/11 (18.2%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Back pain 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 8/43 (18.6%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 6/52 (11.5%) 1/9 (11.1%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/5 (20%)
    Bone pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Flank pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Groin pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Muscle spasms 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Muscle twitching 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Muscular weakness 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Musculoskeletal chest pain 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Musculoskeletal pain 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 5/52 (9.6%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 1/5 (20%)
    Musculoskeletal stiffness 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Myalgia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Neck pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Pain in extremity 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nervous system disorders
    Depressed level of consiousness 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dizziness 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 10/43 (23.3%) 1/11 (9.1%) 1/10 (10%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 1/4 (25%) 9/52 (17.3%) 2/9 (22.2%) 3/8 (37.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Dysgeusia 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 16/43 (37.2%) 3/11 (27.3%) 2/10 (20%) 0/4 (0%) 2/3 (66.7%) 3/3 (100%) 1/4 (25%) 16/52 (30.8%) 3/9 (33.3%) 5/8 (62.5%) 2/5 (40%) 2/4 (50%) 2/3 (66.7%) 1/3 (33.3%) 1/5 (20%)
    Headache 2/4 (50%) 1/3 (33.3%) 0/3 (0%) 7/43 (16.3%) 2/11 (18.2%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 7/52 (13.5%) 2/9 (22.2%) 0/8 (0%) 4/5 (80%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Hyperaesthesia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypoaesthesia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Memory impairment 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Neuropathy peripheral 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Paraesthesia 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Peripheral sensory neuropathy 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/5 (20%)
    Somnolence 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Syncope 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Trigeminal palsy 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Psychiatric disorders
    Abnormal dreams 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Anxiety 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 5/52 (9.6%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/5 (20%)
    Delirium 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Depression 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hallucination 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hallucination, visual 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Insomnia 0/4 (0%) 0/3 (0%) 0/3 (0%) 4/43 (9.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 2/9 (22.2%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Mental status changes 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nightmare 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Stress 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Renal and urinary disorders
    Anuria 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dysuria 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haematuria 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pollakiuria 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urinary incontinence 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Urinary retention 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urine abnormality 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Reproductive system and breast disorders
    Erectile dysfunction 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pelvic pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Penile haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Testicular pain 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vulvovaginal dryness 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Aspiration 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Bronchospasm 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Cough 0/4 (0%) 0/3 (0%) 0/3 (0%) 9/43 (20.9%) 3/11 (27.3%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 3/4 (75%) 8/52 (15.4%) 2/9 (22.2%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/5 (0%)
    Dry throat 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dysphonia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 2/4 (50%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dyspnoea 0/4 (0%) 0/3 (0%) 0/3 (0%) 8/43 (18.6%) 3/11 (27.3%) 2/10 (20%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 13/52 (25%) 3/9 (33.3%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/5 (40%)
    Dysnoea exertional 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Epistaxis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Haemoptysis 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hiccups 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Hypoxia 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nasal congestion 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nasal dryness 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Oropharyngeal pain 1/4 (25%) 1/3 (33.3%) 0/3 (0%) 2/43 (4.7%) 2/11 (18.2%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 2/52 (3.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Painful respiration 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Paranasal sinus hypersecretion 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pharyngeal disorder 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pleural effusion 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Productive cough 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Rhinitis allergic 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Upper-airway cough syndrome 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Wheezing 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/4 (0%) 0/3 (0%) 0/3 (0%) 2/43 (4.7%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Blister 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dermatitis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Dermatitis acneiform 0/4 (0%) 0/3 (0%) 0/3 (0%) 8/43 (18.6%) 1/11 (9.1%) 4/10 (40%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 15/52 (28.8%) 2/9 (22.2%) 4/8 (50%) 1/5 (20%) 2/4 (50%) 1/3 (33.3%) 1/3 (33.3%) 2/5 (40%)
    Dry skin 0/4 (0%) 0/3 (0%) 0/3 (0%) 6/43 (14%) 0/11 (0%) 3/10 (30%) 0/4 (0%) 2/3 (66.7%) 0/3 (0%) 1/4 (25%) 5/52 (9.6%) 3/9 (33.3%) 1/8 (12.5%) 2/5 (40%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 2/5 (40%)
    Erythema 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/4 (25%) 3/52 (5.8%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Exfoliative rash 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hyperhidrosis 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Nail disorder 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Night sweats 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 4/52 (7.7%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pain of skin 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 1/11 (9.1%) 0/10 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Palmar-plantar erythrodysaesthesia 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 1/9 (11.1%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pruritus 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 6/43 (14%) 2/11 (18.2%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/4 (50%) 7/52 (13.5%) 1/9 (11.1%) 1/8 (12.5%) 1/5 (20%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Rash 0/4 (0%) 2/3 (66.7%) 2/3 (66.7%) 9/43 (20.9%) 8/11 (72.7%) 2/10 (20%) 3/4 (75%) 0/3 (0%) 3/3 (100%) 2/4 (50%) 19/52 (36.5%) 3/9 (33.3%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Rash erythematous 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 3/52 (5.8%) 2/9 (22.2%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Rash generalised 1/4 (25%) 0/3 (0%) 1/3 (33.3%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Rash macular 0/4 (0%) 0/3 (0%) 0/3 (0%) 3/43 (7%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Rash maculo-papular 0/4 (0%) 0/3 (0%) 0/3 (0%) 16/43 (37.2%) 3/11 (27.3%) 3/10 (30%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/4 (25%) 12/52 (23.1%) 4/9 (44.4%) 3/8 (37.5%) 4/5 (80%) 0/4 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/5 (20%)
    Rash papular 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/5 (0%)
    Rash pruritic 0/4 (0%) 0/3 (0%) 0/3 (0%) 4/43 (9.3%) 1/11 (9.1%) 0/10 (0%) 0/4 (0%) 2/3 (66.7%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Skin fissures 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 1/11 (9.1%) 1/10 (10%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 2/52 (3.8%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Skin maceration 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Urticaria 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Surgical and medical procedures
    Wound drainage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Vascular disorders
    Deep vein thrombosis 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Flushing 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 1/43 (2.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/5 (0%)
    Haemorrhage 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 1/3 (33.3%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hot flush 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypertension 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/43 (2.3%) 2/11 (18.2%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 1/9 (11.1%) 0/8 (0%) 1/5 (20%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Hypotension 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 4/43 (9.3%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 1/52 (1.9%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 1/5 (20%)
    Lymphoedema 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Pallor 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)
    Thrombophlebitis superficial 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/43 (0%) 0/11 (0%) 0/10 (0%) 0/4 (0%) 0/3 (0%) 1/3 (33.3%) 0/4 (0%) 0/52 (0%) 0/9 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%) 0/3 (0%) 0/3 (0%) 0/5 (0%)

    Limitations/Caveats

    The study was terminated prior to the initiation of Stage 2B and as per changes in planned analysis the data for duration of objective response and PFS were not analyzed.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffman-La Roche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT00996892
    Other Study ID Numbers:
    • MEK4752g
    • GO01330
    First Posted:
    Oct 16, 2009
    Last Update Posted:
    Dec 30, 2016
    Last Verified:
    Nov 1, 2016