A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma

Study Overview
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Brief Summary
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To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.

Official Title
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A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: Placebo
* Drug: Vemurafenib
* Drug: Cobimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist Participants must be naïve to treatment for locally advanced unresectable or metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test Measurable disease per RECIST v1.1 Eastern Clinical Oncology Group performance status of 0 or 1 Consent to provide archival for biomarker analyses Consent to undergo tumor biopsies for biomarker analyses Life expectancy greater than or equal to (≥) 12 weeks Adequate hematologic and end organ function Exclusion Criteria: History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase pathway inhibitor treatment Palliative radiotherapy within 14 days prior to the first dose of study treatment Major surgery or traumatic injury within 14 days prior to first dose of study treatment Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Participants with a previous malignancy within the past 3 years are excluded except for participants with resected basal cell carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast History of or evidence of retinal pathology on ophthalmological examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion, or neovascular macular degeneration Uncontrolled glaucoma with intraocular pressure Serum cholesterol ≥ Grade 2 Hypertriglyceridemia ≥ Grade 2 Hyperglycemia (fasting) ≥ Grade 2 History of clinically significant cardiac dysfunction Participants with active central nervous system (CNS) lesions (including carcinomatous meningitis) are excluded. However, participants are eligible if: All known CNS lesions have been treated with stereotactic therapy or surgery, AND There has been no evidence of clinical and radiographic disease progression in the CNS for ≥ 3 weeks after radiotherapy or surgery Current severe, uncontrolled systemic disease History of malabsorption or other condition that would interfere with absorption of study drugs Pregnant, lactating, or breast feeding women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo + Vemurafenib<br>Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. | Drug: Placebo<br>* Placebo supplied as tablets<br>Drug: Vemurafenib<br>* Vemurafenib supplied as tablets<br>* Other names: RO518426;|
| Experimental: Cobimetinib + Vemurafenib<br>Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. | Drug: Vemurafenib<br>* Vemurafenib supplied as tablets<br>* Other names: RO518426;Drug: Cobimetinib<br>* Cobimetinib supplied as tablets<br>* Other names: XL518;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from randomization until the date of death from any cause. | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | 
| Percentage of Participants With an Objective Response | An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions. | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | 
| Duration of Response | Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. | Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RG7204, Roche RAF inhibitor, BRAF V600E kinase inhibitor, Oncogenic BRAF inhibitor, Zelboraf, vemurafenib, PLX4032, Genentech MEK inhibitor, Genentech BRAF inhibitor, Roche MEK inhibitor, Roche BRAF inhibitor, RO5185426, metastatic melanoma, BRAF positive melanoma, BRAF mutant melanoma, advanced melanoma, Genentech RAF inhibitor, BRAF kinase inhibitor, GDC-0973, XL518, melanoma