Malignant Melanoma
Conditions
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.
Interventions
DRUGCobimetinib
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.
DRUGvemurafenib
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 1. be previously untreated for locally advanced/unresectable or metastatic melanoma or 2. previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or 3. 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 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 | — |
| 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 | — |
| 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 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Australia, United States
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 details
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
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib PD Participants 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. | 66 |
| BRAFi-naïve Participants 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. | 63 |
| Cobimetinib Monotherapy (100 mg or 60 mg) 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. | 2 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 53 | 34 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Progressive disease | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 0 |
Baseline characteristics
| Characteristic | Vemurafenib PD Participants | BRAFi-naïve Participants | Cobimetinib Monotherapy (100 mg or 60 mg) | Total |
|---|---|---|---|---|
| Age, Continuous | 53.0 years STANDARD_DEVIATION 14.8 | 54.0 years STANDARD_DEVIATION 13 | 62.5 years STANDARD_DEVIATION 9.2 | 53.6 years STANDARD_DEVIATION 13.9 |
| Sex: Female, Male Female | 24 Participants | 28 Participants | 1 Participants | 53 Participants |
| Sex: Female, Male Male | 42 Participants | 35 Participants | 1 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 64 / 66 | 63 / 63 | 2 / 2 |
| serious Total, serious adverse events | 21 / 66 | 36 / 63 | 0 / 2 |
Outcome results
Primary
Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 2280 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 90 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1990 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 99 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1790 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 88 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1300 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 35 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1850 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 35 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1600 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 2300 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 100 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1410 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1220 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 63 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1 | 1530 nanograms*hours per milliliter (ng*h/mL) | Geometric Coefficient of Variation 65 |
Primary
AUC0-24 of Cobimetinib on Day 14, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 5180 ng*h/mL | Geometric Coefficient of Variation 170 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 4800 ng*h/mL | Geometric Coefficient of Variation 76 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 3540 ng*h/mL | Geometric Coefficient of Variation 83 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 4500 ng*h/mL | Geometric Coefficient of Variation 17 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 7020 ng*h/mL | Geometric Coefficient of Variation 27 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 3820 ng*h/mL | Geometric Coefficient of Variation 48 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 6360 ng*h/mL | Geometric Coefficient of Variation 46 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 3520 ng*h/mL | Geometric Coefficient of Variation 35 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 5790 ng*h/mL | Geometric Coefficient of Variation 36 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 2540 ng*h/mL | Geometric Coefficient of Variation 84 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 14, Cycle 1 | 3220 ng*h/mL | Geometric Coefficient of Variation 124 |
Primary
AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3 | 727 ng*h/mL | Standard Deviation 556 |
Primary
Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1
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
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 11.6 Liters per hour (L/h) | Geometric Coefficient of Variation 170 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 12.5 Liters per hour (L/h) | Geometric Coefficient of Variation 76 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 17.0 Liters per hour (L/h) | Geometric Coefficient of Variation 83 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 13.3 Liters per hour (L/h) | Geometric Coefficient of Variation 17 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 8.55 Liters per hour (L/h) | Geometric Coefficient of Variation 27 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 21.0 Liters per hour (L/h) | Geometric Coefficient of Variation 48 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 15.7 Liters per hour (L/h) | Geometric Coefficient of Variation 46 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 17.0 Liters per hour (L/h) | Geometric Coefficient of Variation 35 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 13.8 Liters per hour (L/h) | Geometric Coefficient of Variation 36 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 23.6 Liters per hour (L/h) | Geometric Coefficient of Variation 84 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1 | 18.6 Liters per hour (L/h) | Geometric Coefficient of Variation 124 |
Primary
Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 342 ng/mL | Geometric Coefficient of Variation 130 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 307 ng/mL | Geometric Coefficient of Variation 75 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 232 ng/mL | Geometric Coefficient of Variation 80 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 239 ng/mL | Geometric Coefficient of Variation 14 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 414 ng/mL | Geometric Coefficient of Variation 16 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 195 ng/mL | Geometric Coefficient of Variation 48 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 383 ng/mL | Geometric Coefficient of Variation 50 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 215 ng/mL | Geometric Coefficient of Variation 19 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 350 ng/mL | Geometric Coefficient of Variation 37 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 177 ng/mL | Geometric Coefficient of Variation 74 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 200 ng/mL | Geometric Coefficient of Variation 91 |
Primary
Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3 | 51.6 ng/mL | Standard Deviation 50.1 |
Primary
Cmax of Vemurafenib on Day 14, Cycle 1
Time frame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 34.7 mcg/mL | Geometric Coefficient of Variation 41 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 29.4 mcg/mL | Geometric Coefficient of Variation 25 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 43.7 mcg/mL | Geometric Coefficient of Variation 37 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 31.7 mcg/mL | Geometric Coefficient of Variation 42 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 51.3 mcg/mL | Geometric Coefficient of Variation 14 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 43.6 mcg/mL | Geometric Coefficient of Variation 45 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 30.6 mcg/mL | Geometric Coefficient of Variation 53 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 40.9 mcg/mL | Geometric Coefficient of Variation 20 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 33.7 mcg/mL | Geometric Coefficient of Variation 16 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 33.3 mcg/mL | Geometric Coefficient of Variation 58 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 14, Cycle 1 | 36.3 mcg/mL | Geometric Coefficient of Variation 29 |
Primary
Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population.Here, number of participants analyzed = participants who were BRAFi-naïve participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 3.99 mcg/mL | Geometric Coefficient of Variation 73 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 2.31 mcg/mL | — |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 4.16 mcg/mL | Geometric Coefficient of Variation 78 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 1.25 mcg/mL | — |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 2.55 mcg/mL | Geometric Coefficient of Variation 170 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 2.60 mcg/mL | Geometric Coefficient of Variation 70 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 2.78 mcg/mL | Geometric Coefficient of Variation 57 |
Primary
Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were BRAFi-naïve participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants | 2.08 mcg/mL | Standard Deviation 1.64 |
Primary
Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Time frame: Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Population: PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 36.4 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 58 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 34.3 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 34 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 60.9 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 32 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 56.0 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 16 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 36.4 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 19 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 48.2 micrograms per milliliter (mcg/mL) | — |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 40.9 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 110 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 48.6 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 37 |
Primary
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
Time frame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Population: PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | 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 | 38.8 mcg/mL | Standard Deviation 9.61 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | 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 | 48.8 mcg/mL | Standard Deviation 35.4 |
Primary
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: 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 | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 159 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 110 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 146 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 100 |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 121 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 96 |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 136 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 81 |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 130 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 133 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 146 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 79 |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 93.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26 |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 84.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 67 |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1 | 105 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 64 |
Primary
Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES
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
Population: Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES | Cobimetinib dose (21/7 dosing schedule) | 60 mg |
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES | Vemurafenib dose (21/7 dosing schedule) | 960 mg |
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 1 participants |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 2 participants |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 0 participants |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts | 1 participants |
Primary
Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.00 hours |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.0 hours |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.00 hours |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 2.03 hours |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 3.99 hours |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.02 hours |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.03 hours |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 3.05 hours |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.00 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.00 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1 | 4.00 hours |
Primary
Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 2.0 hours |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 3.98 hours |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.02 hours |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.00 hours |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 6.00 hours |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 6.0 hours |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.03 hours |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.08 hours |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.00 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.04 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1 | 4.00 hours |
Primary
Tmax of Vemurafenib on Day 14, Cycle 1
Time frame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Population: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.98 hours |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 2.15 hours |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.95 hours |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.98 hours |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 0.33 hours |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 5.6 hours |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.05 hours |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.83 hours |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.85 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.17 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 14, Cycle 1 | 1.90 hours |
Primary
Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Population: PK population. Here, number of participants analyzed = participants who were BRAFi-naïve participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 5.2 hours |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 4.15 hours |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 5.17 hours |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 5.33 hours |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 2.08 hours |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 4.00 hours |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 4.00 hours |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants | 4.00 hours |
Primary
Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Time frame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Population: PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 2.42 hours |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 2.50 hours |
| DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 3.69 hours |
| DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 4.55 hours |
| DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 2.03 hours |
| DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 1.65 hours |
| DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 1.92 hours |
| DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 0.83 hours |
| DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 2.33 hours |
| CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib | Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study | 1.93 hours |
Secondary
Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Baseline (n=63,63) | 8.75 Percent change in FDG-PET | Standard Deviation 5.55 |
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Percent Change at Cycle 2 (Days 14+7) (n=50,56) | -33.09 Percent change in FDG-PET | Standard Deviation 35.18 |
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Percent Change at Cycle 1 (Days 10-14) (n=59,60) | -43.33 Percent change in FDG-PET | Standard Deviation 26 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Baseline (n=63,63) | 8.19 Percent change in FDG-PET | Standard Deviation 5 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Percent Change at Cycle 2 (Days 14+7) (n=50,56) | -70.73 Percent change in FDG-PET | Standard Deviation 17.05 |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2 | Percent Change at Cycle 1 (Days 10-14) (n=59,60) | -65.74 Percent change in FDG-PET | Standard Deviation 14.82 |
Secondary
Median Duration of Response (DOR)
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Median Duration of Response (DOR) | 6.8 months |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Median Duration of Response (DOR) | 14.3 months |
Secondary
Overall Survival (OS)
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Overall Survival (OS) | 8.5 months |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Overall Survival (OS) | 31.8 months |
Secondary
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
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | 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 | 15.2 percentage of participants |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | 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 | 87.3 percentage of participants |
Secondary
Percentage of Participants With Disease Progression According to RECIST V 1.1
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Percentage of Participants With Disease Progression According to RECIST V 1.1 | 36.4 percentage of participants |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Percentage of Participants With Disease Progression According to RECIST V 1.1 | 3.2 percentage of participants |
Secondary
Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)
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)
Population: Number of participants analyzed=number of participants available for analysis of this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib | Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC) | 7 participants |
| DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib | Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC) | 5 participants |