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

Phase 3

Completed

Conditions: Malignant Melanoma

Interventions: Drug: Placebo
Drug: Vemurafenib
Drug: Cobimetinib

Registration Number: NCT01689519

Lead Sponsor: Hoffmann-La Roche

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 495

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:
1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND
2. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + Vemurafenib	Vemurafenib	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.
Placebo + Vemurafenib	Placebo	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.
Cobimetinib + Vemurafenib	Vemurafenib	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.
Cobimetinib + Vemurafenib	Cobimetinib	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)	Overall survival was defined as the time from randomization until the date of death from any cause.
Percentage of Participants With an Objective Response	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)	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.
Duration of Response	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)	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.

Trial Locations

Locations (156): University of Alabama at Birmingham
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Birmingham, Alabama, United States
The Angeles Clinic and Research Institute - W LA Office
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Los Angeles, California, United States
University of California Davis Health System
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Sacramento, California, United States
Sutter Pacific Medical Foundation
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Santa Rosa, California, United States
University Of Colorado
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Aurora, Colorado, United States
Florida Cancer Specialists - Broadway
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Fort Myers, Florida, United States
Mount Sinai Medical Center
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Miami Beach, Florida, United States
Orlando Health Inc.
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Orlando, Florida, United States
Northwestern Center For Clinical Research
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Chicago, Illinois, United States
Uni of Kansas Medical Center; Dept of Neurology
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Kansas City, Kansas, United States
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University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States