Back to resultsA Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
Primary Purpose
Malignant Melanoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Cobimetinib
vemurafenib
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Melanoma
Eligibility Criteria
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
Sites / Locations
- UCLA Department of Medicine
- University of California at San Francisco
- The Angeles Clinic and Research Institute, Santa Monica Office
- University of Colorado; Anschutz Cancer Pavilion
- University of Chicago
- Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology
- Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building
- New York University Medical Center
- Vanderbilt University Medical Center
- Peter Maccallum Cancer Institute; Medical Oncology
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Arm 12
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
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
Cobimetinib Monotherapy (100 mg or 60 mg)
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Arm Description
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
AUC0-24 of Cobimetinib on Day 14, Cycle 1
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.
Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
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
Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Cmax of Vemurafenib on Day 14, Cycle 1
Tmax of Vemurafenib on Day 14, Cycle 1
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
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
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)
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)
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
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)
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01271803
Brief Title
A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
February 17, 2011 (Actual)
Primary Completion Date
October 1, 2013 (Actual)
Study Completion Date
December 12, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
131 (Actual)
8. Arms, Groups, and Interventions
Arm Title
DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
Cobimetinib Monotherapy (100 mg or 60 mg)
Arm Type
Experimental
Arm Description
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.
Arm Title
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Arm Title
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cobimetinib
Other Intervention Name(s)
GDC-0973
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
vemurafenib
Intervention Description
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.
Primary Outcome Measure Information:
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
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
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
Title
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
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
Time Frame
Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Title
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
Title
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
Title
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
Title
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
Title
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
Title
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
Secondary Outcome Measure Information:
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)
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)
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)
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)
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)
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Department of Medicine
City
Los Angeles
State/Province
California
ZIP/Postal Code
90024
Country
United States
Facility Name
University of California at San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
The Angeles Clinic and Research Institute, Santa Monica Office
City
Santa Monica
State/Province
California
ZIP/Postal Code
90025
Country
United States
Facility Name
University of Colorado; Anschutz Cancer Pavilion
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10036
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Peter Maccallum Cancer Institute; Medical Oncology
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
12. IPD Sharing Statement
Citations:
PubMed Identifier
32746839
Citation
Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.
Results Reference
derived
PubMed Identifier
25037139
Citation
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15. Erratum In: Lancet Oncol. 2014 Sep;15(10):417.
Results Reference
derived
PubMed Identifier
22651703
Citation
Baudy AR, Dogan T, Flores-Mercado JE, Hoeflich KP, Su F, van Bruggen N, Williams SP. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973. EJNMMI Res. 2012 May 31;2(1):22. doi: 10.1186/2191-219X-2-22.
Results Reference
derived
Learn more about this trial
A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma
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