A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01271803
Collaborator
(none)
131
10
12
81.8
13.1
0.2
Study Details
Study Description
Brief Summary
This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
131 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 Evaluating the Safety, Tolerability and Pharmacokinetics of Vemurafenib in Combination With GDC-0973 (Cobimetinib) When Administered in BRAFV600E Mutation-Positive Patients Previously Treated (But Without Prior Exposure to BRAF or MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic Melanoma or Those Who Have Progressed After Treatment With Vemurafenib
Actual Study Start Date
:
Feb 17, 2011
Actual Primary Completion Date
:
Oct 1, 2013
Actual Study Completion Date
:
Dec 12, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: Cobimetinib Monotherapy (100 mg or 60 mg) Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
|
| Experimental: CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
| Experimental: CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. |
Drug: Cobimetinib
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Other Names:
Drug: vemurafenib
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts [28 Days]
DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count [ANC] less than <500/microliter [μL]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
- Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES [28 Days]
The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC <500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
- Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 [Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3 [Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 [Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 [Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3 [Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 [Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14]
- Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 [Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14]
- AUC0-24 of Cobimetinib on Day 14, Cycle 1 [Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14]
- Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 [Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14]
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
- Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study [Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1]
- Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study [Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1]
- Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study [Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1]
- Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants [Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants [Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants [Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1]
- Cmax of Vemurafenib on Day 14, Cycle 1 [Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14]
- Tmax of Vemurafenib on Day 14, Cycle 1 [Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14]
Secondary Outcome Measures
- Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1 [Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)]
Tumor response of CR or PR is considered as objective response. 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.
- Percentage of Participants With Disease Progression According to RECIST V 1.1 [Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)]
Progressive disease (PD) according to RECIST V 1.1: at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (nadir), including baseline; in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of 1 or more lesions is also considered as progression.
- Median Duration of Response (DOR) [Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 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 v 1.1, or death from any cause during the study (that is within 30 days after the last dose of study treatment).
- Overall Survival (OS) [Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)]
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up. OS analyzed using Kaplan-Meier estimate.
- Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 [Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)]
The pharmacodynamic effect of cobimetinib in combination with vemurafenib was assessed by measuring changes in FDG uptake as characterized by the lean body mass corrected (LBM) maximum standardized uptake value (SUV max) measurement using FDG-PET. Post-baseline timepoint Cycle 1 was averaged between Days 10 to 14 and Cycle 2 for Days 14+7.
- Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC) [At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months)]
Changes in effector molecules of the MAPK pathway that are directly or indirectly affected by BRAF and MEK inhibition (including but not limited to ERK and phosphorylated ERK and MEK) by IHC using biopsies at baseline, between Days 10-14 of Cycle 1, and at disease progression. IHC is a staining process performed on fresh/frozen tumor tissue samples.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])
-
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
-
Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1
-
Participants must
-
be previously untreated for locally advanced/unresectable or metastatic melanoma or
-
previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or
-
progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or expanded access programs (EAP) immediately prior to enrollment in this study or
-
progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.
- Life expectancy >/=12 weeks
Exclusion Criteria:
-
History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
-
Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
-
Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
-
Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UCLA Department of Medicine | Los Angeles | California | United States | 90024 |
| 2 | University of California at San Francisco | San Francisco | California | United States | 94115 |
| 3 | The Angeles Clinic and Research Institute, Santa Monica Office | Santa Monica | California | United States | 90025 |
| 4 | University of Colorado; Anschutz Cancer Pavilion | Aurora | Colorado | United States | 80045 |
| 5 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 6 | Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology | Indianapolis | Indiana | United States | 46202 |
| 7 | Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building | Detroit | Michigan | United States | 48201 |
| 8 | New York University Medical Center | New York | New York | United States | 10036 |
| 9 | Vanderbilt University Medical Center | Nashville | Tennessee | United States | 37232 |
| 10 | Peter Maccallum Cancer Institute; Medical Oncology | Melbourne | Victoria | Australia | 3000 |
Sponsors and Collaborators
- Hoffmann-La Roche
Investigators
- Study Director: Clinical Trials, Hoffmann-La Roche
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01271803
Other Study ID Numbers:
- NO25395
First Posted:
Jan 7, 2011
Last Update Posted:
Jul 29, 2019
Last Verified:
Jul 1, 2019
Study Results
Participant Flow
| Recruitment Details | Study included two stages. Stage 1: dose escalation stage (DES), consisted of 9 "Cobimetinib + Vemurafenib" combination arms and 1 Cobimetinib monotherapy. Stage 2: cohort expansion stage (CES), consisted of 2 "Cobimetinib + Vemurafenib" combination arms, treated with recommended phase 2 dose. |
|---|---|
| Pre-assignment Detail | Participants data were pooled across dose/regimen cohorts from two stages and analyzed separately per final analysis for vemurafenib-PD and BRAFi-naive participants who received cobimetinib and vemurafenib. Data is presented based on the final CSR. As of 2017 per-cohort data were not collected |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) |
|---|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Period Title: Overall Study | |||
| STARTED | 66 | 63 | 2 |
| COMPLETED | 11 | 24 | 0 |
| NOT COMPLETED | 55 | 39 | 2 |
Baseline Characteristics
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | Total |
|---|---|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Total of all reporting groups |
| Overall Participants | 66 | 63 | 2 | 131 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
53.0
(14.8)
|
54.0
(13.0)
|
62.5
(9.2)
|
53.6
(13.9)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
24
36.4%
|
28
44.4%
|
1
50%
|
53
40.5%
|
| Male |
42
63.6%
|
35
55.6%
|
1
50%
|
78
59.5%
|
Outcome Measures
| Title | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts |
|---|---|
| Description | DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count [ANC] less than <500/microliter [μL]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase. |
| Time Frame | 28 Days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety-evaluable population (SEP) included all participants who received at least one dose of study drug. SEP participants who received combination study treatment (cobimetinib + Vemurafenib) were included in the analysis of this outcome. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 27 | 3 | 4 | 4 | 4 | 3 | 5 |
| Number [participants] |
0
0%
|
0
0%
|
1
50%
|
0
0%
|
2
NaN
|
0
NaN
|
0
NaN
|
0
NaN
|
1
NaN
|
| Title | Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES |
|---|---|
| Description | The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC <500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase. |
| Time Frame | 28 Days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Dose Escalation Stage (Stage 1) |
|---|---|
| Arm/Group Description | All participants who received vemurafenib and cobimetinib in any dose combination during DES, until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 63 |
| Cobimetinib dose (21/7 dosing schedule) |
60
|
| Vemurafenib dose (21/7 dosing schedule) |
960
|
| Title | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population included all participants who received study treatment and had at least one vemurafenib and cobimetinib plasma concentration available. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 26 | 3 | 4 | 4 | 4 | 5 | 27 | 38 |
| Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)] |
159
(110)
|
146
(100)
|
121
(96)
|
136
(81)
|
130
(53)
|
133
(37)
|
146
(79)
|
93.6
(26)
|
84.3
(67)
|
105
(64)
|
| Title | Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 2 |
| Mean (Standard Deviation) [ng/mL] |
51.6
(50.1)
|
| Title | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 26 | 3 | 4 | 4 | 4 | 2 | 5 | 27 | 38 |
| Median (Full Range) [hours] |
4.00
|
4.0
|
4.00
|
2.03
|
3.99
|
4.02
|
4.03
|
3.05
|
4.00
|
4.00
|
4.00
|
| Title | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 26 | 3 | 4 | 4 | 4 | 5 | 27 | 38 |
| Geometric Mean (Geometric Coefficient of Variation) [nanograms*hours per milliliter (ng*h/mL)] |
2280
(90)
|
1990
(99)
|
1790
(88)
|
1300
(35)
|
1850
(35)
|
1600
(29)
|
2300
(100)
|
1410
(29)
|
1220
(63)
|
1530
(65)
|
| Title | AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 2 |
| Mean (Standard Deviation) [ng*h/mL] |
727
(556)
|
| Title | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
342
(130)
|
307
(75)
|
232
(80)
|
239
(14)
|
414
(16)
|
195
(48)
|
383
(50)
|
215
(19)
|
350
(37)
|
177
(74)
|
200
(91)
|
| Title | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Median (Full Range) [hours] |
2.0
|
3.98
|
4.02
|
4.00
|
6.00
|
6.0
|
4.03
|
4.08
|
4.00
|
4.04
|
4.00
|
| Title | AUC0-24 of Cobimetinib on Day 14, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
5180
(170)
|
4800
(76)
|
3540
(83)
|
4500
(17)
|
7020
(27)
|
3820
(48)
|
6360
(46)
|
3520
(35)
|
5790
(36)
|
2540
(84)
|
3220
(124)
|
| Title | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 |
|---|---|
| Description | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Time Frame | Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [Liters per hour (L/h)] |
11.6
(170)
|
12.5
(76)
|
17.0
(83)
|
13.3
(17)
|
8.55
(27)
|
21.0
(48)
|
15.7
(46)
|
17.0
(35)
|
13.8
(36)
|
23.6
(84)
|
18.6
(124)
|
| Title | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 6 | 8 | 3 | 3 | 1 | 15 | 19 |
| Geometric Mean (Geometric Coefficient of Variation) [micrograms per milliliter (mcg/mL)] |
36.4
(58)
|
34.3
(34)
|
60.9
(32)
|
56.0
(16)
|
36.4
(19)
|
48.2
(NA)
|
40.9
(110)
|
48.6
(37)
|
| Title | Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study. |
| Arm/Group Title | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib |
|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 2 | 2 |
| Mean (Standard Deviation) [mcg/mL] |
38.8
(9.61)
|
48.8
(35.4)
|
| Title | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 6 | 8 | 2 | 3 | 2 | 3 | 1 | 15 | 19 |
| Median (Full Range) [hours] |
2.42
|
2.50
|
3.69
|
4.55
|
2.03
|
1.65
|
1.92
|
0.83
|
2.33
|
1.93
|
| Title | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population.Here, number of participants analyzed = participants who were BRAFi-naïve participants. |
| Arm/Group Title | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 16 | 1 | 3 | 1 | 3 | 11 | 19 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg/mL] |
3.99
(73)
|
2.31
(NA)
|
4.16
(78)
|
1.25
(NA)
|
2.55
(170)
|
2.60
(70)
|
2.78
(57)
|
| Title | Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were BRAFi-naïve participants. |
| Arm/Group Title | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib |
|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 2 |
| Mean (Standard Deviation) [mcg/mL] |
2.08
(1.64)
|
| Title | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were BRAFi-naïve participants. |
| Arm/Group Title | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 2 | 16 | 1 | 3 | 1 | 3 | 11 | 19 |
| Median (Full Range) [hours] |
5.2
|
4.15
|
5.17
|
5.33
|
2.08
|
4.00
|
4.00
|
4.00
|
| Title | Cmax of Vemurafenib on Day 14, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg/mL] |
34.7
(41)
|
29.4
(25)
|
43.7
(37)
|
31.7
(42)
|
51.3
(14)
|
43.6
(45)
|
30.6
(53)
|
40.9
(20)
|
33.7
(16)
|
33.3
(58)
|
36.3
(29)
|
| Title | Tmax of Vemurafenib on Day 14, Cycle 1 |
|---|---|
| Description | |
| Time Frame | Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK population. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. |
| Measure Participants | 5 | 8 | 25 | 3 | 3 | 3 | 4 | 3 | 3 | 25 | 32 |
| Median (Full Range) [hours] |
1.98
|
2.15
|
1.95
|
1.98
|
0.33
|
5.6
|
1.05
|
1.83
|
1.85
|
1.17
|
1.90
|
| Title | Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1 |
|---|---|
| Description | Tumor response of CR or PR is considered as objective response. 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 | Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy evaluable population who had measurable disease at baseline and had either a post-baseline tumour assessment or progressed before any tumour assessment was included in the analysis of this outcome. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 66 | 63 |
| Number (95% Confidence Interval) [percentage of participants] |
15.2
23%
|
87.3
138.6%
|
| Title | Percentage of Participants With Disease Progression According to RECIST V 1.1 |
|---|---|
| Description | Progressive disease (PD) according to RECIST V 1.1: at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (nadir), including baseline; in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of 1 or more lesions is also considered as progression. |
| Time Frame | Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy evaluable population who had measurable disease at baseline and had either a post-baseline tumour assessment or progressed before any tumour assessment was included in the analysis of this outcome. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 66 | 63 |
| Number [percentage of participants] |
36.4
55.2%
|
3.2
5.1%
|
| Title | Median Duration of Response (DOR) |
|---|---|
| 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 v 1.1, or death from any cause during the study (that is within 30 days after the last dose of study treatment). |
| Time Frame | Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy evaluable population who had measurable disease at baseline and had either a post-baseline tumour assessment or progressed before any tumour assessment was included in the analysis of this outcome. Number of participants analysed who were evaluated for this outcome measure. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 10 | 55 |
| Median (95% Confidence Interval) [months] |
6.8
|
14.3
|
| Title | Overall Survival (OS) |
|---|---|
| Description | OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up. OS analyzed using Kaplan-Meier estimate. |
| Time Frame | Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Efficacy evaluable population who had measurable disease at baseline and had either a post-baseline tumour assessment or progressed before any tumour assessment was included in the analysis of this outcome. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 66 | 63 |
| Median (Full Range) [months] |
8.5
|
31.8
|
| Title | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 |
|---|---|
| Description | The pharmacodynamic effect of cobimetinib in combination with vemurafenib was assessed by measuring changes in FDG uptake as characterized by the lean body mass corrected (LBM) maximum standardized uptake value (SUV max) measurement using FDG-PET. Post-baseline timepoint Cycle 1 was averaged between Days 10 to 14 and Cycle 2 for Days 14+7. |
| Time Frame | Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety evaluable population who received combination study treatment (Cobimetinib + Vemurafenib) was included in the analysis of this outcome. Here, number of participants analyzed = participants who were evaluable for this outcome. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 63 | 63 |
| Baseline (n=63,63) |
8.75
(5.55)
|
8.19
(5.00)
|
| Percent Change at Cycle 1 (Days 10-14) (n=59,60) |
-43.33
(26.00)
|
-65.74
(14.82)
|
| Percent Change at Cycle 2 (Days 14+7) (n=50,56) |
-33.09
(35.18)
|
-70.73
(17.05)
|
| Title | Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC) |
|---|---|
| Description | Changes in effector molecules of the MAPK pathway that are directly or indirectly affected by BRAF and MEK inhibition (including but not limited to ERK and phosphorylated ERK and MEK) by IHC using biopsies at baseline, between Days 10-14 of Cycle 1, and at disease progression. IHC is a staining process performed on fresh/frozen tumor tissue samples. |
| Time Frame | At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Number of participants analyzed=number of participants available for analysis of this outcome measure. |
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants |
|---|---|---|
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. |
| Measure Participants | 7 | 5 |
| Number [participants] |
7
10.6%
|
5
7.9%
|
Adverse Events
| Time Frame | Up to 82 months | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety data was not reported per dose/regimen cohort. Due to final analysis data for adverse events were reported collectively for both the reporting groups- Vemurafenib PD and BRAFi-naïve participants along with Cobimetinib Monotherapy. Data is presented based on the final CSR. As of 2017 per-cohort data were not collected. | |||||
| Arm/Group Title | Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | |||
| Arm/Group Description | All participants who progressed on vemurafenib monotherapy immediately prior to enrollment into this study were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | All participants who were previously untreated or previously treated but naïve to BRAF or MEK inhibitor therapy were considered as BRAFi-naïve participants. These participants were treated with vemurafenib in combination with cobimetinib at a particular dose combination and dosing schedule depending on the cohort in which they were enrolled until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. | Participants received oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria were met. | |||
All Cause Mortality |
||||||
| Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 21/66 (31.8%) | 36/63 (57.1%) | 0/2 (0%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Febrile neutropenia | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Cardiac disorders | ||||||
| Congestive cardiomyopathy | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Acute myocardial infarction | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Atrial fibrillation | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Cardiomyopathy | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Endocrine disorders | ||||||
| Hyperthyroidism | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Eye disorders | ||||||
| Iridocyclitis | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Vogt-koyanagi-harada syndrome | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Chorioretinopathy | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Uveitis | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Gastrointestinal disorders | ||||||
| Gastrointestinal haemorrhage | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Nausea | 1/66 (1.5%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Constipation | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Gastrooesophageal reflux disease | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Haemtemesis | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Vomiting | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| General disorders | ||||||
| Pyrexia | 1/66 (1.5%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Face Oedema | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Hepatobiliary disorders | ||||||
| Biloma | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Immune system disorders | ||||||
| Hypersenstivity | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Infections and infestations | ||||||
| Pneumonia | 2/66 (3%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Ophthalmic herpes zoster | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Pneumonia chlamydial | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Sepsis | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Urinary tract infection | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Cellulitis | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Streptococcal bacteraemia | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Wound infection | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Bacteraemia | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Staphylococcal sepsis | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Viral infection | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Femur fracture | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Spinal compression fracture | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Investigations | ||||||
| Electrocardiogram QT prolonged | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Dehydration | 1/66 (1.5%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Hyponatraemia | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Flank pain | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Squamous cell carcinoma of skin | 4/66 (6.1%) | 7/63 (11.1%) | 0/2 (0%) | |||
| Keratoacanthoma | 1/66 (1.5%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Basal cell carcinoma | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Tonsil cancer | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Adrenal neoplasm | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Bowen's disease | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Breast cancer | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Renal cell carcinoma | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Nervous system disorders | ||||||
| Syncope | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Seizure | 1/66 (1.5%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Brain oedema | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Psychiatric disorders | ||||||
| Mental status changes | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Suicidal ideation | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Anxiety | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Renal and urinary disorders | ||||||
| Renal failure | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Glomerulonephritis | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Haematuria | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Nephrolithiasis | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Acute kidney injury | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Tubulointerstitial nephritis | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pleural effusion | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Pulmonary embolism | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Rash maculo-papular | 0/66 (0%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Photosensitivity reaction | 1/66 (1.5%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Dermatitis acneiform | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Surgical and medical procedures | ||||||
| Salpingo-Oophorectomy unilateral | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Vascular disorders | ||||||
| Hypotension | 1/66 (1.5%) | 0/63 (0%) | 0/2 (0%) | |||
| Hypertension | 0/66 (0%) | 1/63 (1.6%) | 0/2 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 64/66 (97%) | 63/63 (100%) | 2/2 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 11/66 (16.7%) | 23/63 (36.5%) | 0/2 (0%) | |||
| Thrombocytopenia | 3/66 (4.5%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Neutropenia | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Eye disorders | ||||||
| Vision blurred | 2/66 (3%) | 14/63 (22.2%) | 0/2 (0%) | |||
| Photophobia | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Visual impairment | 4/66 (6.1%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Lacrimation increased | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Gastrointestinal disorders | ||||||
| Diarrhoea | 31/66 (47%) | 52/63 (82.5%) | 2/2 (100%) | |||
| Nausea | 22/66 (33.3%) | 37/63 (58.7%) | 1/2 (50%) | |||
| Vomiting | 13/66 (19.7%) | 30/63 (47.6%) | 1/2 (50%) | |||
| Abdominal pain | 10/66 (15.2%) | 13/63 (20.6%) | 1/2 (50%) | |||
| Constipation | 10/66 (15.2%) | 13/63 (20.6%) | 1/2 (50%) | |||
| Abdominal distension | 6/66 (9.1%) | 3/63 (4.8%) | 1/2 (50%) | |||
| Dry mouth | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Stomatitis | 0/66 (0%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Abdominal pain upper | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Ascites | 4/66 (6.1%) | 0/63 (0%) | 0/2 (0%) | |||
| Gastrooesophageal reflux disease | 0/66 (0%) | 5/63 (7.9%) | 1/2 (50%) | |||
| Rectal haemorrhage | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Dyspepsia | 2/66 (3%) | 9/63 (14.3%) | 0/2 (0%) | |||
| General disorders | ||||||
| Fatigue | 18/66 (27.3%) | 46/63 (73%) | 1/2 (50%) | |||
| Oedema peripheral | 11/66 (16.7%) | 27/63 (42.9%) | 1/2 (50%) | |||
| Pyrexia | 11/66 (16.7%) | 27/63 (42.9%) | 0/2 (0%) | |||
| Chills | 10/66 (15.2%) | 17/63 (27%) | 1/2 (50%) | |||
| Mucosal inflammation | 3/66 (4.5%) | 5/63 (7.9%) | 1/2 (50%) | |||
| Asthenia | 5/66 (7.6%) | 2/63 (3.2%) | 0/2 (0%) | |||
| Chest pain | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Malaise | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Influenza like illness | 1/66 (1.5%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Peripheral swelling | 3/66 (4.5%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Infections and infestations | ||||||
| Upper respiratory tract infection | 6/66 (9.1%) | 16/63 (25.4%) | 0/2 (0%) | |||
| Folliculitis | 0/66 (0%) | 7/63 (11.1%) | 1/2 (50%) | |||
| Urinary tract infection | 3/66 (4.5%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Nasopharyngitis | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Sinusitis | 0/66 (0%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Sunburn | 13/66 (19.7%) | 23/63 (36.5%) | 0/2 (0%) | |||
| Investigations | ||||||
| Blood alkaline phophatase increased | 10/66 (15.2%) | 22/63 (34.9%) | 1/2 (50%) | |||
| Blood creatine phosphokinase increased | 10/66 (15.2%) | 30/63 (47.6%) | 1/2 (50%) | |||
| Aspartate aminotransferase increased | 6/66 (9.1%) | 22/63 (34.9%) | 0/2 (0%) | |||
| Alanine aminotransferase increased | 4/66 (6.1%) | 25/63 (39.7%) | 0/2 (0%) | |||
| Blood creatinine increased | 6/66 (9.1%) | 21/63 (33.3%) | 0/2 (0%) | |||
| Blood bilirubin increased | 6/66 (9.1%) | 9/63 (14.3%) | 0/2 (0%) | |||
| Electrocardiogram QT prolonged | 4/66 (6.1%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Weight decreased | 3/66 (4.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Gamma-glutamyl transferase increased | 1/66 (1.5%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Lymphocyte count decreased | 3/66 (4.5%) | 7/63 (11.1%) | 0/2 (0%) | |||
| Blood uric acid increased | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Transaminases increased | 0/66 (0%) | 4/63 (6.3%) | 1/2 (50%) | |||
| Weight increased | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 14/66 (21.2%) | 17/63 (27%) | 1/2 (50%) | |||
| Hypokalaemia | 4/66 (6.1%) | 16/63 (25.4%) | 0/2 (0%) | |||
| Hypoalbuminaemia | 4/66 (6.1%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Hyponatraemia | 3/66 (4.5%) | 9/63 (14.3%) | 0/2 (0%) | |||
| Hyperuricaemia | 0/66 (0%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Hypocalcaemia | 4/66 (6.1%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Hypercalcaemia | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Hyperglycaemia | 2/66 (3%) | 10/63 (15.9%) | 0/2 (0%) | |||
| Hypophosphataemia | 3/66 (4.5%) | 13/63 (20.6%) | 0/2 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 8/66 (12.1%) | 31/63 (49.2%) | 0/2 (0%) | |||
| Myalgia | 4/66 (6.1%) | 20/63 (31.7%) | 0/2 (0%) | |||
| Pain in extremity | 4/66 (6.1%) | 11/63 (17.5%) | 1/2 (50%) | |||
| Back pain | 10/66 (15.2%) | 7/63 (11.1%) | 1/2 (50%) | |||
| Musculoskeletal pain | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Muscular weakness | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Neck pain | 4/66 (6.1%) | 3/63 (4.8%) | 0/2 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Seborrhoeic keratosis | 1/66 (1.5%) | 15/63 (23.8%) | 1/2 (50%) | |||
| Skin papilloma | 0/66 (0%) | 15/63 (23.8%) | 0/2 (0%) | |||
| Basal cell carcinoma | 2/66 (3%) | 11/63 (17.5%) | 1/2 (50%) | |||
| Melanocytic naevus | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Nervous system disorders | ||||||
| Headache | 13/66 (19.7%) | 19/63 (30.2%) | 0/2 (0%) | |||
| Dizziness | 9/66 (13.6%) | 9/63 (14.3%) | 0/2 (0%) | |||
| Paraesthesia | 5/66 (7.6%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Dysgeusia | 2/66 (3%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Memory impairment | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Seizure | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Psychiatric disorders | ||||||
| Depression | 4/66 (6.1%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Anxiety | 3/66 (4.5%) | 7/63 (11.1%) | 0/2 (0%) | |||
| Insomnia | 3/66 (4.5%) | 8/63 (12.7%) | 0/2 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 6/66 (9.1%) | 13/63 (20.6%) | 1/2 (50%) | |||
| Dyspnoea | 8/66 (12.1%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Oropharyngeal pain | 2/66 (3%) | 11/63 (17.5%) | 0/2 (0%) | |||
| Dyspnoea exertional | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Nasal congestion | 0/66 (0%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Photosensitivity reaction | 12/66 (18.2%) | 44/63 (69.8%) | 0/2 (0%) | |||
| Rash | 18/66 (27.3%) | 33/63 (52.4%) | 1/2 (50%) | |||
| Pruritus | 7/66 (10.6%) | 19/63 (30.2%) | 0/2 (0%) | |||
| Dermatitis acneiform | 6/66 (9.1%) | 22/63 (34.9%) | 1/2 (50%) | |||
| Dry skin | 2/66 (3%) | 17/63 (27%) | 0/2 (0%) | |||
| Erythema | 2/66 (3%) | 16/63 (25.4%) | 0/2 (0%) | |||
| Alopecia | 7/66 (10.6%) | 9/63 (14.3%) | 1/2 (50%) | |||
| Hyperkeratosis | 2/66 (3%) | 10/63 (15.9%) | 0/2 (0%) | |||
| Actinic keratosis | 3/66 (4.5%) | 19/63 (30.2%) | 0/2 (0%) | |||
| Rash maculo-papular | 3/66 (4.5%) | 20/63 (31.7%) | 0/2 (0%) | |||
| Rash macular | 2/66 (3%) | 9/63 (14.3%) | 0/2 (0%) | |||
| Skin lesion | 3/66 (4.5%) | 7/63 (11.1%) | 0/2 (0%) | |||
| Rash erythematous | 3/66 (4.5%) | 7/63 (11.1%) | 0/2 (0%) | |||
| Vitiligo | 1/66 (1.5%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Acne | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Keratosis pilaris | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Dermatitis | 2/66 (3%) | 6/63 (9.5%) | 0/2 (0%) | |||
| Erythema nodosum | 2/66 (3%) | 5/63 (7.9%) | 0/2 (0%) | |||
| Hyperhidrosis | 4/66 (6.1%) | 1/63 (1.6%) | 0/2 (0%) | |||
| Pain of skin | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Panniculitis | 2/66 (3%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Rash generalised | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Rosacea | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Rash papular | 1/66 (1.5%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Rash pruritic | 0/66 (0%) | 4/63 (6.3%) | 0/2 (0%) | |||
| Vascular disorders | ||||||
| Hypertension | 6/66 (9.1%) | 18/63 (28.6%) | 1/2 (50%) | |||
| Lymphoedema | 0/66 (0%) | 6/63 (9.5%) | 0/2 (0%) | |||
Limitations/Caveats
[Not Specified]
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 |
| genentech@druginfo.com |
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01271803
Other Study ID Numbers:
- NO25395
First Posted:
Jan 7, 2011
Last Update Posted:
Jul 29, 2019
Last Verified:
Jul 1, 2019