Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Vemurafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

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 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.

Cobimetinib

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.

vemurafenib

Clinical Trials

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.

A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma

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

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.

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.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

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.

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.

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).

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.

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.

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.

Hoffmann-La Roche

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.

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.

Vemurafenib PD 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.

BRAFi-naïve Participants

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.

Cobimetinib Monotherapy (100 mg or 60 mg)

Total

Age, Continuous

Sex: Female, Male

Demographic data was not reported across dose/regimen cohort per final analysis, as it was pooled across separately 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

Medical Communications

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.

DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib

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.

DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

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.

DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

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.

DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib

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.

DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib

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.

DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib

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.

DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib

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.

DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib

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.

DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

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.

Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts

Cobimetinib dose (21/7 dosing schedule)

Vemurafenib dose (21/7 dosing schedule)

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.

Dose Escalation Stage (Stage 1)

Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome.

Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES

CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib

CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib

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.

Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1

PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.

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

PK population. Here, number of participants analyzed = participants who were previously treated with vemurafenib prior to enrollment into this study.

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

PK population.Here, number of participants analyzed = participants who were BRAFi-naïve participants.

Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants

PK population. Here, number of participants analyzed = participants who were 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

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.

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

Percentage of Participants With Disease Progression According to RECIST V 1.1

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.

Median Duration of Response (DOR)

Overall Survival (OS)

Baseline (n=63,63)

Percent Change at Cycle 1 (Days 10-14) (n=59,60)

Percent Change at Cycle 2 (Days 14+7) (n=50,56)

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.

Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2

Number of participants analyzed=number of participants available for analysis of this outcome measure.

Spots Global Cancer Trial Database for A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

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