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A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0973 in Combination With GDC-0068 When Administered in Participants With Locally Advanced or Metastatic Solid Tumors

Sponsor
Genentech, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01562275
Collaborator
(none)
67
Enrollment
5
Locations
3
Arms
33
Duration (Months)
13.4
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This open-label, multicenter, Phase Ib dose-escalation study will evaluate the safety, tolerability and pharmacokinetics of oral dosing of GDC-0973 and GDC-0068 administered in combination in patients with locally advanced or metastatic solid tumors. Cohorts of patients will receive multiple ascending doses of GDC-0973 and GDC-0068. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
67 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib, Open-Label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of GDC-0973 and GDC-0068 in Patients With Locally Advanced or Metastatic Solid Tumors
Study Start Date :
Apr 1, 2012
Actual Primary Completion Date :
Jan 1, 2015
Actual Study Completion Date :
Jan 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dose escalation stage 1 (Arm A): Cobimetinib and Ipatasertib

Participants will receive cobimetinib (GDC-0973) capsules (at a starting dose of 40 mg) and ipatasertib (GDC-0068) capsules (at a starting dose of 200 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: Ipatasertib
multiple doses
Other Names:
  • GDC-0068

    • Drug: Cobimetinib
    multiple doses
    Other Names:
  • GDC-0973

    		•
    Experimental: Dose escalation stage 1 (Arm B): Cobimetinib and Ipatasertib

    Participants will receive cobimetinib (GDC-0973) capsules (at a starting dose of 100 mg) on Days 1, 4, 8, 11, 15, and 18 and ipatasertib (GDC-0068) capsules (at a starting dose of 200 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: Ipatasertib
    multiple doses
    Other Names:
  • GDC-0068

    • Drug: Cobimetinib
    multiple doses
    Other Names:
  • GDC-0973

    		•
    Experimental: Stage 2 (Indication specific dose expansion cohort)

    Participants will receive cobimetinib (GDC-0973) capsules on Days 1, 4, 8, 11, 15, and 18 and ipatasertib (GDC-0068) 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 phosphatase and tensin homolog (PTEN)-loss triple-negative breast cancer and PTEN-loss endometrial carcinoma.

    Drug: Ipatasertib
    multiple doses
    Other Names:
  • GDC-0068

    • Drug: Cobimetinib
    multiple doses
    Other Names:
  • GDC-0973

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose Limiting Toxicities (DLTs) [Cycle 1 (28 Days)]

      DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) Grade (G) ≥3 febrile neutropenia, b) G ≥4 neutropenia (absolute neutrophil count [ANC] <500/ microliter [μL]) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or alkaline phosphatase (ALP) lasting >3 days, f) Hepatic transaminases >3 × Upper Limit of Normal (ULN) and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days.

    2. Number of DLTs Categorized as Per the Nature [Cycle 1 (28 Days)]

      DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) G ≥3 febrile neutropenia, b) G ≥4 neutropenia (ANC <500/μL) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or ALP lasting >3 days, f) Hepatic transaminases >3 × ULN and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days. Hematologic, Hepatic and non-hematologic and non-hepatic DLT categories were to be reported.

    3. Maximum Tolerated Doses (MTDs) in Combination of Cobimetinib and Ipatasertib During Dose-Escalation Stage 1 [Cycle 1 (28 Days)]

      An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. On the basis of AEs that did not meet protocol-defined DLT criteria (defined in Outcome measure 1) but indicated intolerability of a given dose combination, the combination MTDs were determined (as per investigator) during Stage 1 of the study.

    4. Number of Participants With At Least One AE Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version (V) 4.0 [From Baseline up to 30 days after the last dose of study treatment or until initiation of another anticancer treatment whichever occurred first (Up to 33 months)]

      AE was defined in Outcome Measure 3. AEs were graded as per NCI CTCAE V 4.0 as follows: G 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily living (ADL) (instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money and others); G 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL (refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden); G 4: Life-threatening consequences, urgent intervention indicated; G 5: Death related to AE. If a participant had multiple events of different grades, the highest grade that occurred in that participant was counted.

    Secondary Outcome Measures

    1. Area Under Concentration-Time Curve From Time Zero to Last Measurable Concentration After Dose [AUC0-Last] of Ipatasertib and Cobimetinib on Day 1 and Day 15 [Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1]

    2. Maximum Plasma Concentration (Cmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15 [Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1]

    3. Time Taken to Reach Cmax (Tmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15 [Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1]

    4. Last Measurable Concentration (Clast) of Ipatasertib and Cobimetinib on Day 1 and Day 15 [Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1]

    5. Number of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)]

      RECIST v1.1 (for measurable disease), CR: disappearance of all target lesions, reduction in short axis <10 millimeters in pathological lymph nodes (target and non-target lesions); PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Responses were confirmed by repeat assessments ≥4 weeks after initial documentation.

    6. Duration of Objective Response for Participants With Measurable Disease According to RECIST v1.1 [Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)]

      Duration of response, defined as the time from first occurrence of a documented objective response until the time of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).

    7. Progression-Free Survival (PFS) Time for Participants With Measurable Disease According to RECIST v1.1 [Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)]

      PFS is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).

    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 therapies either do not exist or have proven ineffective or intolerable

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

    • Life expectancy >/= 12 weeks

    • Adequate hematologic and end organ function

    Exclusion Criteria:

    • History of prior significant toxicity from another MEK pathway inhibitor requiring discontinuation of treatment

    • History of prior significant toxicity from another phosphoinositide 3-kinase (PI3K) or Akt pathway or mammalian target of rapamycin (mTOR) inhibitor requiring discontinuation of treatment

    • Anti-cancer therapy within 28 days prior to first dose of study drug, except as stated in protocol

    • History of type I or type II diabetes mellitus requiring insulin

    • Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary, or metabolic disease)

    • Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, hepatitis B or hepatitis C virus

    • Active autoimmune disease

    • Pregnant or lactating women

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

    • History of glaucoma

    • History of retinal vein occlusion

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Boston Massachusetts United States 02215
    2 Detroit Michigan United States 48201
    3 Nashville Tennessee United States 37203
    4 Barcelona Spain 08035
    5 Valencia Spain 46010

    Sponsors and Collaborators

    • Genentech, Inc.

    Investigators

    • Study Director: Clinical Trials, Genentech, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT01562275
    Other Study ID Numbers:
    • GE28079
    • 2012-003934-18
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Mar 28, 2016
    Last Verified:
    Feb 1, 2016
    Keywords provided by Genentech, Inc.
    GDC0973
    MEK
    MEK inhibitor
    GDC0068
    Akt
    Akt inhibitor

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Study included two stages. Stage 1: dose escalation cohorts (DEC), consisted of Arm A (concurrent 21 day dosing followed by 7 day dosing holiday) and Arm B (intermittent dosing). Stage 2: indication specific expansion cohorts (PTEN-low endometrial carcinoma and PTEN-low triple-negative breast cancer) treated with recommended phase 2 dose.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 milligrams (mg) cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Period Title: Stage 1
    STARTED 3 7 3 4 4 4 3 7 3 7 3 0 0
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 3 7 3 4 4 4 3 7 3 7 3 0 0
    Period Title: Stage 1
    STARTED 0 0 0 0 0 0 0 0 0 0 0 14 5
    COMPLETED 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 14 5

    Baseline Characteristics

    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib Total
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Total of all reporting groups
    Overall Participants 3 7 3 4 4 4 3 7 3 7 3 14 5 67
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.0
    (3.5)
    59.1
    (8.7)
    58.3
    (5.5)
    66.8
    (16.5)
    62.3
    (7.0)
    51.8
    (10.9)
    59.0
    (9.2)
    58.6
    (11.9)
    61.0
    (13.7)
    57.6
    (10.9)
    52.7
    (24.9)
    62.9
    (8.7)
    49.0
    (10.1)
    59.0
    (11.0)
    Sex: Female, Male (Count of Participants)
    Female
    2
    66.7%
    4
    57.1%
    1
    33.3%
    3
    75%
    3
    75%
    4
    100%
    2
    66.7%
    3
    42.9%
    2
    66.7%
    4
    57.1%
    1
    33.3%
    14
    100%
    5
    100%
    48
    71.6%
    Male
    1
    33.3%
    3
    42.9%
    2
    66.7%
    1
    25%
    1
    25%
    0
    0%
    1
    33.3%
    4
    57.1%
    1
    33.3%
    3
    42.9%
    2
    66.7%
    0
    0%
    0
    0%
    19
    28.4%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose Limiting Toxicities (DLTs)
    Description DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) Grade (G) ≥3 febrile neutropenia, b) G ≥4 neutropenia (absolute neutrophil count [ANC] <500/ microliter [μL]) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or alkaline phosphatase (ALP) lasting >3 days, f) Hepatic transaminases >3 × Upper Limit of Normal (ULN) and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days.
    Time Frame Cycle 1 (28 Days)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis set included all participants who received at least 1 dose of study treatment. This outcome was analyzed in safety analysis population participants in dose escalation cohorts.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 3 4 4 4 3 7 3 6 3
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Number of DLTs Categorized as Per the Nature
    Description DLT is defined as 1 of the following toxicities considered by the investigator to be possibly related to study drugs: a) G ≥3 febrile neutropenia, b) G ≥4 neutropenia (ANC <500/μL) lasting >5 days , c) G ≥4 thrombocytopenia lasting >2 days, d) G ≥4 anemia, e) G ≥3 elevation of total bilirubin or hepatic transaminase or ALP lasting >3 days, f) Hepatic transaminases >3 × ULN and an increase in total bilirubin >2 × ULN without any findings of cholestasis and in the absence of other contributory factors, g) G ≥2 visual changes that do not resolve to baseline within 14 days, h) 1 episode of fasting G 4 hyperglycemia or 3 episodes of fasting, i) G 3 hyperglycemia on separate days within 7 days, j) G ≥4 fasting hypercholesterolemia or triglyceridemia for ≥2 weeks, k) G ≥3 nausea, vomiting, or diarrhea despite maximal supportive medications lasting for ≥3 days. Hematologic, Hepatic and non-hematologic and non-hepatic DLT categories were to be reported.
    Time Frame Cycle 1 (28 Days)

    Outcome Measure Data

    Analysis Population Description
    Data for this outcome measure was not analyzed as no participant experienced DLT.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0
    3. Primary Outcome
    Title Maximum Tolerated Doses (MTDs) in Combination of Cobimetinib and Ipatasertib During Dose-Escalation Stage 1
    Description An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. On the basis of AEs that did not meet protocol-defined DLT criteria (defined in Outcome measure 1) but indicated intolerability of a given dose combination, the combination MTDs were determined (as per investigator) during Stage 1 of the study.
    Time Frame Cycle 1 (28 Days)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis population participants from dose escalation cohorts.
    Arm/Group Title Stage 1 DECs
    Arm/Group Description During Stage 1, participants received cobimetinib and ipatasertib combination doses either under Arm A (21/7 dosing schedule [cobimetinib and ipatasertib taken concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days]) or under Arm B (intermittent cobimetinib dosing schedule [ipatasertib taken once daily on Days 1-21 consecutively with concurrent dosing of cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days)] until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 48
    Arm A Cobimetinib dose
    60
    Arm A Ipatasertib dose
    200
    Arm B Cobimetinib dose
    150
    Arm B Ipatasertib dose
    300
    4. Primary Outcome
    Title Number of Participants With At Least One AE Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version (V) 4.0
    Description AE was defined in Outcome Measure 3. AEs were graded as per NCI CTCAE V 4.0 as follows: G 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G 2: minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily living (ADL) (instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money and others); G 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated, disabling, limiting self care ADL (refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden); G 4: Life-threatening consequences, urgent intervention indicated; G 5: Death related to AE. If a participant had multiple events of different grades, the highest grade that occurred in that participant was counted.
    Time Frame From Baseline up to 30 days after the last dose of study treatment or until initiation of another anticancer treatment whichever occurred first (Up to 33 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis population.
    Arm/Group Title DECs and Expansion Cohorts
    Arm/Group Description Included all participants who were treated under Stage 1 (Dose Escalation Cohorts) and Stage 2 (Dose Expansion Cohorts).
    Measure Participants 66
    Grade 1 (G 1)
    4
    133.3%
    Grade 2 (G 2)
    15
    500%
    Grade 3 (G 3)
    36
    1200%
    Grade 4 (G 4)
    1
    33.3%
    Grade 5 (G 5)
    10
    333.3%
    5. Secondary Outcome
    Title Area Under Concentration-Time Curve From Time Zero to Last Measurable Concentration After Dose [AUC0-Last] of Ipatasertib and Cobimetinib on Day 1 and Day 15
    Description
    Time Frame Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis population: Included all participants who received study treatment and had at least 1 cobimetinib and ipatasertib plasma concentration available. "n" represents the number of participants who were evaluable for that particular assessment.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 2 4 4 4 3 6 2 6 2 14 5
    Ipatasertib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    688
    (106)
    538
    (33.8)
    1760
    (NA)
    2170
    (74.9)
    255
    (203)
    956
    (43.5)
    1420
    (46.4)
    790
    (78.8)
    838
    (239)
    424
    (67.9)
    2030
    (46.4)
    1450
    (48.7)
    1540
    (11.3)
    Ipatasertib Day 15 (n=3,6,2,1,4,3,1,6,2,5,2,7,2)
    703
    (40.8)
    781
    (20.7)
    2440
    (45.2)
    1750
    (NA)
    599
    (133)
    1760
    (62.3)
    2230
    (NA)
    1260
    (85.2)
    668
    (148)
    866
    (58.1)
    3390
    (9.70)
    1070
    (65.2)
    1270
    (13.3)
    Cobimetinib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    1500
    (320)
    1130
    (68.6)
    5050
    (NA)
    1920
    (87.8)
    3740
    (139)
    5580
    (54.4)
    2690
    (50.7)
    2710
    (60.7)
    13600
    (111)
    3270
    (89.2)
    4330
    (39.3)
    11400
    (64.1)
    10800
    (41.0)
    Cobimetinib Day 15 (n=3,6,2,1,4,3,1,6,1,5,2,7,2)
    3250
    (223)
    3260
    (48.6)
    7080
    (91.1)
    2500
    (NA)
    3230
    (96.8)
    8140
    (5.65)
    4400
    (NA)
    4970
    (65.5)
    8570
    (NA)
    3980
    (111)
    6830
    (38.4)
    8880
    (64.8)
    1480
    (10800)
    6. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15
    Description
    Time Frame Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis population. "n" represents the number of participants who were evaluable for that particular assessment.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 2 4 4 4 3 6 2 6 2 14 5
    Ipatasertib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    137
    (244)
    97.1
    (92.2)
    300
    (NA)
    336
    (118)
    42.9
    (560)
    156
    (32.8)
    329
    (104)
    141
    (34.3)
    99.9
    (254)
    95.8
    (57.1)
    262
    (122)
    268
    (48.3)
    374
    (48.2)
    Ipatasertib Day 15 (n=3,6,2,1,4,3,1,6,2,5,2,7,2)
    94.5
    (55.0)
    130
    (47.1)
    386
    (58.4)
    137
    (NA)
    86.9
    (237)
    165
    (33.9)
    441
    (NA)
    170
    (64.4)
    72.9
    (200)
    114
    (53.9)
    450
    (16.9)
    149
    (113)
    156
    (12.7)
    Cobimetinib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    134
    (333)
    78.6
    (73.2)
    312
    (NA)
    109
    (85.4)
    259
    (192)
    405
    (45.9)
    192
    (50.3)
    220
    (64.9)
    1040
    (151)
    262
    (59.9)
    249
    (46.0)
    799
    (55.8)
    840
    (56.6)
    Cobimetinib Day 15 (n=3,6,2,1,4,3,1,6,1,5,2,7,2)
    222
    (182)
    215
    (61.4)
    407
    (72.6)
    121
    (NA)
    217
    (135)
    511
    (14.6)
    376
    (NA)
    320
    (64.5)
    481
    (NA)
    253
    (103)
    420
    (41.4)
    704
    (75.2)
    84.2
    (7940)
    7. Secondary Outcome
    Title Time Taken to Reach Cmax (Tmax) of Ipatasertib and Cobimetinib on Day 1 and Day 15
    Description
    Time Frame Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis population. "n" represents the number of participants who were evaluable for that particular assessment.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 2 4 4 4 3 6 2 6 2 14 5
    Ipatasertib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    1.03
    1.02
    1.00
    1.04
    1.00
    3.04
    1.00
    2.00
    3.17
    1.08
    1.52
    1.47
    1.00
    Ipatasertib Day 15 (n=3,6,2,1,4,3,1,6,2,5,2,7,2)
    2.03
    1.03
    1.04
    6.05
    1.04
    1.00
    1.00
    1.19
    1.57
    1.00
    0.98
    1.08
    0.97
    Cobimetinib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    2.00
    3.97
    2.05
    3.83
    3.04
    3.03
    4.05
    4.00
    24.0
    3.91
    5.92
    3.08
    2.08
    Cobimetinib Day 15 (n=3,6,2,1,4,3,1,6,1,5,2,7,2)
    2.25
    3.92
    3.01
    6.05
    4.78
    4.03
    1.88
    4.06
    5.92
    4.00
    13.1
    2.00
    1.96
    8. Secondary Outcome
    Title Last Measurable Concentration (Clast) of Ipatasertib and Cobimetinib on Day 1 and Day 15
    Description
    Time Frame Predose (0 hour), 1, 2, 4, 6 and 24 hours postdose on Day 1 and Day 15 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis population. "n" represents the number of participants who were evaluable for that particular assessment.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 2 4 4 4 3 6 2 6 2 14 5
    Ipatasertib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    6.18
    (4.90)
    6.07
    (1.99)
    23.7
    (NA)
    25.1
    (11.3)
    4.32
    (2.60)
    13.4
    (8.29)
    15.2
    (5.15)
    7.05
    (11.60)
    18.2
    (16.2)
    6.00
    (4.18)
    30.0
    (5.66)
    18.0
    (10.1)
    15.4
    (6.38)
    Ipatasertib Day 15 (n=3,6,2,1,4,3,1,6,2,5,2,7,2)
    14.1
    (4.54)
    11.6
    (1.79)
    38.0
    (14.5)
    30.6
    (NA)
    12.8
    (6.85)
    30.6
    (22.2)
    39.3
    (NA)
    21.90
    (45.50)
    13.0
    (7.66)
    16.9
    (10.9)
    54.7
    (15.5)
    20.7
    (12.1)
    14.5
    (8.68)
    Cobimetinib Day 1 (n=3,7,1,4,4,4,3,5,2,6,2,14,5)
    79.4
    (119)
    35.9
    (10.5)
    150
    (NA)
    71.9
    (44.0)
    122
    (76.5)
    204
    (172)
    72.6
    (30.7)
    145
    (159)
    1280
    (1120)
    125
    (127)
    160
    (17.7)
    386
    (237)
    268
    (146)
    Cobimetinib Day 15 (n=3,6,2,1,4,3,1,6,1,5,2,7,2)
    228
    (319)
    105
    (58.3)
    251
    (192)
    93.8
    (NA)
    123
    (70.2)
    294
    (158)
    127
    (NA)
    186
    (116)
    283
    (NA)
    204
    (254)
    280
    (53.0)
    299
    (172)
    227
    (316)
    9. Secondary Outcome
    Title Number of Participants With Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    Description RECIST v1.1 (for measurable disease), CR: disappearance of all target lesions, reduction in short axis <10 millimeters in pathological lymph nodes (target and non-target lesions); PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Responses were confirmed by repeat assessments ≥4 weeks after initial documentation.
    Time Frame Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)

    Outcome Measure Data

    Analysis Population Description
    Safety analysis population.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 3 7 3 4 4 4 3 7 3 6 3 14 5
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    1
    25%
    0
    0%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    10. Secondary Outcome
    Title Duration of Objective Response for Participants With Measurable Disease According to RECIST v1.1
    Description Duration of response, defined as the time from first occurrence of a documented objective response until the time of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).
    Time Frame Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)

    Outcome Measure Data

    Analysis Population Description
    This outcome measure was not analyzed as per changes in planned analysis due to very few participants with measurable response.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0
    11. Secondary Outcome
    Title Progression-Free Survival (PFS) Time for Participants With Measurable Disease According to RECIST v1.1
    Description PFS is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST 1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).
    Time Frame Screening, Days 21-28 of Cycle 2, Day 25 (± 3 days) of Cycle 4 and every 8 weeks thereafter till study completion (Up to 33 months)

    Outcome Measure Data

    Analysis Population Description
    This outcome measure was not analyzed as per changes in planned analysis due to very few participants with measurable response.
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    Measure Participants 0 0 0 0 0 0 0 0 0 0 0 0 0

    Adverse Events

    Time Frame From Baseline up to 30 days after the last dose of study treatment or until initiation of another anticancer treatment whichever occurred first (Up to 33 months)
    Adverse Event Reporting Description
    Arm/Group Title DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    Arm/Group Description Participants received oral 40 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 200 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 60 mg cobimetinib and 300 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 40 mg cobimetinib and 400 mg ipatasertib concurrently once daily on Days 1-21, with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 125 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 175 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 200 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 150 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants received oral 400 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 100 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with endometrial carcinoma received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. Participants with triple negative breast cancer received oral 300 mg ipatasertib once daily on Days 1-21 consecutively with concurrent dosing of 140 mg cobimetinib on Days 1, 4, 8, 11, 15, and 18 with a 7-day dosing holiday on Days 22-28, every 28 days (1 Cycle=28 Days) until disease progression, unacceptable toxicity, or any other discontinuation criteria were met.
    All Cause Mortality
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    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)
    Serious Adverse Events
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    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 1/3 (33.3%) 2/7 (28.6%) 0/3 (0%) 2/4 (50%) 1/4 (25%) 3/4 (75%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 2/6 (33.3%) 2/3 (66.7%) 10/14 (71.4%) 2/5 (40%)
    Cardiac disorders
    Atrial Fibrillation 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Bradycardia 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Gastrointestinal disorders
    Abdominal Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Diarrhoea 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Enterocolitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Gastrointestinal Haemorrhage 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Intestinal Obstruction 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Large Intestinal Obstruction 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Nausea 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Small Intestinal Obstruction 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Vomiting 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    General disorders
    Disease Progression 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Fatigue 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pyrexia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hepatobiliary disorders
    Bile Duct Obstruction 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Infections and infestations
    Clostridium Difficile Colitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Pneumonia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pyelonephritis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Sepsis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Injury, poisoning and procedural complications
    Hip Fracture 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Toxicity to Various Agents 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 1/5 (20%)
    Investigations
    Liver Function Test Abnormal 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 2/14 (14.3%) 0/5 (0%)
    Hyperkalaemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Musculoskeletal and connective tissue disorders
    Back Pain 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Neoplasm Progression 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 1/5 (20%)
    Nervous system disorders
    Presyncope 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Psychiatric disorders
    Mental Status Changes 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Renal and urinary disorders
    Renal Failure 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Renal Failure Acute 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pneumonia Aspiration 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Pneumonitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pulmonary Embolism 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Respiratory Distress 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Respiratory Failure 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 1/5 (20%)
    Vascular disorders
    Haematoma 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hypotension 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Other (Not Including Serious) Adverse Events
    DEC Arm A: 40 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 200 mg Ipatasertib DEC Arm A: 60 mg Cobimetinib + 300 mg Ipatasertib DEC Arm A: 40 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 125 mg Cobimetinib + 400 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 300 mg Ipatasertib DEC Arm B: 175 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 150 mg Cobimetinib + 200 mg Ipatasertib DEC Arm B: 100 mg Cobimetinib + 400 mg Ipatasertib Endometrial Carcinoma: 140 mg Cobimetinib + 300 mg Ipatasertib Breast Cancer: 140 mg Cobimetinib + 300 mg Ipatasertib
    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 3/3 (100%) 7/7 (100%) 3/3 (100%) 4/4 (100%) 4/4 (100%) 4/4 (100%) 3/3 (100%) 7/7 (100%) 3/3 (100%) 6/6 (100%) 3/3 (100%) 14/14 (100%) 5/5 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 4/7 (57.1%) 1/3 (33.3%) 1/4 (25%) 3/4 (75%) 3/4 (75%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 2/3 (66.7%) 6/14 (42.9%) 1/5 (20%)
    Anaemia Vitamin B12 Deficiency 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hypercoagulation 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Leukocytosis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Leukopenia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Lymphopenia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Neutropenia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Thrombocytopenia 0/3 (0%) 3/7 (42.9%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Cardiac disorders
    Atrial Fibrillation 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Atrial Flutter 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Bradycardia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Palpitations 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Sinus Bradycardia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Sinus Tachycardia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Supraventricular Tachycardia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Tachycardia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Eye disorders
    Eye Discharge 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Eye Disorder 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Eye Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Lacrimation Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Ocular Hyperaemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Periorbital Oedema 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Photopsia 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Vision Blurred 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 3/6 (50%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Visual Acuity Reduced Transiently 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Visual Impairment 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Vitreous Floaters 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Gastrointestinal disorders
    Abdominal Discomfort 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Abdominal Distension 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 3/14 (21.4%) 0/5 (0%)
    Abdominal Pain 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 2/7 (28.6%) 0/3 (0%) 2/6 (33.3%) 1/3 (33.3%) 3/14 (21.4%) 1/5 (20%)
    Abdominal Pain Lower 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Abdominal Pain Upper 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 2/6 (33.3%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Anal Haemorrhage 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Aphthous Stomatitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Ascites 1/3 (33.3%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 1/5 (20%)
    Chapped Lips 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Colitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Constipation 1/3 (33.3%) 4/7 (57.1%) 1/3 (33.3%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 5/14 (35.7%) 2/5 (40%)
    Diarrhoea 3/3 (100%) 6/7 (85.7%) 3/3 (100%) 4/4 (100%) 4/4 (100%) 3/4 (75%) 3/3 (100%) 7/7 (100%) 3/3 (100%) 4/6 (66.7%) 3/3 (100%) 14/14 (100%) 5/5 (100%)
    Dry Mouth 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Dyspepsia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Eructation 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Flatulence 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 3/14 (21.4%) 0/5 (0%)
    Gastrooesophageal Reflux Disease 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Haematochezia 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Ileus Paralytic 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Lip Dry 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Lip Oedema 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Nausea 2/3 (66.7%) 4/7 (57.1%) 2/3 (66.7%) 4/4 (100%) 3/4 (75%) 2/4 (50%) 1/3 (33.3%) 4/7 (57.1%) 1/3 (33.3%) 6/6 (100%) 3/3 (100%) 11/14 (78.6%) 4/5 (80%)
    Obstruction Gastric 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oesophageal Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oral Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oral Pruritus 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pancreatitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Paraesthesia Oral 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Peptic Ulcer 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Proctalgia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Retching 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Stomatitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 5/14 (35.7%) 1/5 (20%)
    Tongue Oedema 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Vomiting 2/3 (66.7%) 4/7 (57.1%) 2/3 (66.7%) 4/4 (100%) 3/4 (75%) 3/4 (75%) 2/3 (66.7%) 3/7 (42.9%) 2/3 (66.7%) 5/6 (83.3%) 3/3 (100%) 12/14 (85.7%) 3/5 (60%)
    Haemorrhoids 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    General disorders
    Asthenia 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 2/4 (50%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 4/14 (28.6%) 4/5 (80%)
    Catheter Site Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Chest Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Chills 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Early Satiety 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Face Oedema 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Fatigue 3/3 (100%) 3/7 (42.9%) 1/3 (33.3%) 2/4 (50%) 2/4 (50%) 1/4 (25%) 2/3 (66.7%) 4/7 (57.1%) 1/3 (33.3%) 4/6 (66.7%) 3/3 (100%) 5/14 (35.7%) 1/5 (20%)
    Gait Disturbance 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Malaise 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Medical Device Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Mucosal inflammation 0/3 (0%) 3/7 (42.9%) 0/3 (0%) 2/4 (50%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 1/3 (33.3%) 1/14 (7.1%) 0/5 (0%)
    Non-cardiac Chest Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oedema Peripheral 2/3 (66.7%) 2/7 (28.6%) 0/3 (0%) 2/4 (50%) 3/4 (75%) 2/4 (50%) 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Peripheral Swelling 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pyrexia 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 1/14 (7.1%) 0/5 (0%)
    Systemic Inflammatory Response Syndrome 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Immune system disorders
    Contrast Media Allergy 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hypersensitivity 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Infections and infestations
    Acute Sinusitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 1/5 (20%)
    Bacteraemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Bronchitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Candida Infection 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Cellulitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Clostridium Difficile Colitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Cystitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hordeolum 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Infected Skin Ulcer 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 1/5 (20%)
    Influenza 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Localised Infection 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Mucosal Infection 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oral Candidiasis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Paronychia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pharyngitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Upper Respiratory Tract Infection 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Urinary Tract Infection 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 2/4 (50%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 1/3 (33.3%) 3/14 (21.4%) 1/5 (20%)
    Vaginal Infection 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Viral Infection 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Injury, poisoning and procedural complications
    Animal Bite 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Fall 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Laceration 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Investigations
    Alanine Aminotransferase Increased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 1/14 (7.1%) 1/5 (20%)
    Amylase Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Aspartate Aminotransferase Increased 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 2/14 (14.3%) 1/5 (20%)
    Blood Alkaline Phosphatase 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Blood Alkaline Phosphatase Increased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Blood Calcium Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Chloride Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Cholesterol Increased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Creatine Phosphokinase Increased 2/3 (66.7%) 3/7 (42.9%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 2/6 (33.3%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Blood Creatinine Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Creatinine Increased 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 2/3 (66.7%) 1/14 (7.1%) 0/5 (0%)
    Blood Glucose Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Insulin Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Blood Lactate Dehydrogenase Increased 1/3 (33.3%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Blood Sodium Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Urea Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Blood Urea Increased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Blood Uric Acid Increased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Carbohydrate Antigen 15-3 Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Carbon Dioxide Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Cardiac Murmur 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Electrocardiogram QT Prolonged 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Heart Rate Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    High Density Lipoprotein Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Insulin C-peptide Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Lipase Increased 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Lymphocyte Count Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Monocyte Count Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Neutrophil Count Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oxygen Saturation Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Urine Output Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Weight Decreased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    White Blood Cell Count Decreased 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    White Blood Cell Count Increased 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Metabolism and nutrition disorders
    Decreased Appetite 1/3 (33.3%) 4/7 (57.1%) 0/3 (0%) 1/4 (25%) 2/4 (50%) 2/4 (50%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 3/3 (100%) 7/14 (50%) 1/5 (20%)
    Dehydration 1/3 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 1/4 (25%) 2/4 (50%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 1/3 (33.3%) 4/14 (28.6%) 1/5 (20%)
    Gout 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hypercholesterolaemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Hyperglycaemia 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 2/3 (66.7%) 0/14 (0%) 0/5 (0%)
    Hyperkalaemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hypertriglyceridaemia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hyperuricaemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hypoalbuminaemia 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 1/3 (33.3%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Hypocalcaemia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Hypokalaemia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 2/4 (50%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 1/3 (33.3%) 5/14 (35.7%) 1/5 (20%)
    Hypomagnesaemia 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 5/14 (35.7%) 0/5 (0%)
    Hyponatraemia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 3/4 (75%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 3/14 (21.4%) 0/5 (0%)
    Hypophosphataemia 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Malnutrition 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Salt Craving 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 1/14 (7.1%) 0/5 (0%)
    Back Pain 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 2/4 (50%) 1/4 (25%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Bone Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Flank Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Groin Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Muscle Spasms 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Muscular Weakness 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Musculoskeletal Chest Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Musculoskeletal Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Myalgia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Neck Pain 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pain in Extremity 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 2/4 (50%) 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 2/5 (40%)
    Tendonitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Nervous system disorders
    Depressed Level of Consciousness 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Disturbance in Attention 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Dizziness 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 1/4 (25%) 2/4 (50%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 2/5 (40%)
    Dysgeusia 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 2/6 (33.3%) 2/3 (66.7%) 1/14 (7.1%) 2/5 (40%)
    Headache 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 0/4 (0%) 2/4 (50%) 1/4 (25%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Hypoaesthesia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Lethargy 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Memory Impairment 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Migraine with Aura 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Monoplegia 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Paraesthesia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Polyneuropathy 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Sciatica 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Somnolence 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 2/5 (40%)
    Syncope 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 1/14 (7.1%) 0/5 (0%)
    Visual Field Defect 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Psychiatric disorders
    Anxiety 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Confusional State 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Depression 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Hallucination 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hallucination, Visual 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Insomnia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 1/3 (33.3%) 2/14 (14.3%) 0/5 (0%)
    Mental Status Changes 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Renal and urinary disorders
    Bladder Spasm 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Chromaturia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Dysuria 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Haematuria 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hydronephrosis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Incontinence 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Micturition Urgency 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oliguria 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pollakiuria 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Renal Failure 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Renal Failure Acute 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Reproductive system and breast disorders
    Oedema Genital 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pelvic Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pruritus Genital 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Vaginal Discharge 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Vaginal Haemorrhage 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Respiratory, thoracic and mediastinal disorders
    Atelectasis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Cough 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/4 (25%) 2/4 (50%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Dysphonia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 1/5 (20%)
    Dyspnoea 0/3 (0%) 1/7 (14.3%) 1/3 (33.3%) 1/4 (25%) 2/4 (50%) 2/4 (50%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 2/5 (40%)
    Dyspnoea Exertional 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 2/4 (50%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Epistaxis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hiccups 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hypoxia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Nasal Congestion 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Nasal Discomfort 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Oropharyngeal Pain 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Painful Respiration 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pleural Effusion 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 2/4 (50%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 2/14 (14.3%) 0/5 (0%)
    Pneumonitis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Productive Cough 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pulmonary Congestion 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pulmonary Embolism 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Sinus Congestion 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Throat Irritation 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Upper-airway Cough Syndrome 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Wheezing 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Decubitus Ulcer 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Dermatitis Acneiform 0/3 (0%) 2/7 (28.6%) 2/3 (66.7%) 1/4 (25%) 1/4 (25%) 2/4 (50%) 1/3 (33.3%) 7/7 (100%) 3/3 (100%) 5/6 (83.3%) 1/3 (33.3%) 8/14 (57.1%) 2/5 (40%)
    Dry Skin 0/3 (0%) 0/7 (0%) 2/3 (66.7%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hyperhidrosis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Nail Discolouration 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Onychoclasis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Pruritus 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 1/3 (33.3%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Rash 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 3/14 (21.4%) 1/5 (20%)
    Rash Erythematous 1/3 (33.3%) 0/7 (0%) 1/3 (33.3%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Rash Generalised 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 2/5 (40%)
    Rash Macular 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/4 (25%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Rash Maculo-papular 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 1/3 (33.3%) 3/7 (42.9%) 0/3 (0%) 3/6 (50%) 2/3 (66.7%) 2/14 (14.3%) 0/5 (0%)
    Rash Pruritic 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Skin Disorder 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Urticaria 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Surgical and medical procedures
    Sinus Operation 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 1/3 (33.3%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Vascular disorders
    Deep Vein Thrombosis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 1/4 (25%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 1/3 (33.3%) 0/14 (0%) 0/5 (0%)
    Embolism 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Flushing 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hot Flush 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 1/4 (25%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 0/14 (0%) 0/5 (0%)
    Hypertension 0/3 (0%) 2/7 (28.6%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Hypotension 0/3 (0%) 1/7 (14.3%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 1/6 (16.7%) 0/3 (0%) 1/14 (7.1%) 1/5 (20%)
    Lymphoedema 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)
    Subclavian Vein Thrombosis 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/4 (0%) 0/4 (0%) 0/4 (0%) 0/3 (0%) 0/7 (0%) 0/3 (0%) 0/6 (0%) 0/3 (0%) 1/14 (7.1%) 0/5 (0%)

    Limitations/Caveats

    As per changes in the planned analysis, PFS and duration of response outcome measures were not analyzed as only few participants experienced a measurable response.

    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 Hoffmann-LaRoche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Genentech, Inc.
    ClinicalTrials.gov Identifier:
    NCT01562275
    Other Study ID Numbers:
    • GE28079
    • 2012-003934-18
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Mar 28, 2016
    Last Verified:
    Feb 1, 2016