A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma

Study Overview
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Brief Summary
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This is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab + cobimetinib + vemurafenib compared with placebo + cobimetinib + vemurafenib in patients with previously untreated BRAFv600 mutation-positive metastatic or unresectable locally advanced melanoma.

Official Title
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A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma

Conditions
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Melanoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females of child bearing potential and males with female partners must and use of contraceptive methods with a failure rate of less than or equal to (</=)1% per year is required during treatment and for 6 months post treatment. Males should not expose pregnant partners to sperm and refrain from donating sperm for 6 months post treatment. Women must refrain from donating eggs during this same period Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma Naive to prior systemic anti-cancer therapy for melanoma (example: chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies) except adjuvant treatment with interferon (IFN), interleukin (IL)-2, or vaccine therapies or herbal therapies Documentation of BRAFv600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority Eastern Cooperative Oncology Group Performance (ECOG) Status of 0 or 1 Measurable disease according to RECIST v1.1 (must be outside central nervous system (CNS)) Life expectancy >/=18 weeks For participants not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) less than or equal to (</=) 1.5*upper limit of normal (ULN) within 28 days prior to initiation of study treatment For participants receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment Exclusion Criteria: Cancer-Related Exclusion Criteria: Major surgical procedure within 4 weeks prior study treatment initiation Traumatic injury or palliative radiotherapy within 2 weeks prior study treatment initiation Active malignancy (other than BRAFv600 mutation-positive melanoma) or malignancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the participant has been disease-free for at least 3 years Ocular Exclusion Criteria: History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration Cardiac Exclusion Criteria: History of clinically significant cardiac dysfunction Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or below 50% Central Nervous System (CNS) Exclusion Criteria: Untreated or actively progressing CNS lesions (carcinomatous meningitis) History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm); or leptomeningeal metastatic disease; or intracranial hemorrhage Additional Exclusion Criteria: Uncontrolled diabetes or symptomatic hyperglycemia Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer History of malabsorption or other clinically significant metabolic dysfunction Pregnant or breastfeeding, or intending to become pregnant during the study Prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis, organizing pneumonia (example: bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan Active or history of autoimmune disease or immune deficiency Known clinically significant liver disease, inherited liver disease and active viral disease Active tuberculosis Treatment with therapeutic oral or intravenous (IV) antibiotics; or with a live, attenuated vaccine; or systemic immunosuppressive medication Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the atezolizumab, cobimetinib, or vemurafenib formulations Any grade >/=3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of study treatment

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo<br>Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first. | Drug: Atezolizumab<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Cobimetinib<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Vemurafenib<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Vemurafenib Placebo<br>* Will be administered as per the schedule described in individual arm.<br>|
| Experimental: Atezolizumab Placebo + Cobimetinib + Vemurafenib<br>Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first. | Drug: Atezolizumab Placebo<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Cobimetinib<br>* Will be administered as per the schedule described in individual arm.<br>Drug: Vemurafenib<br>* Will be administered as per the schedule described in individual arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1 | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1 | Objective response is defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1 | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Duration of Response, as Determined by Investigator Using RECIST v1.1 | DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Overall Survival | OS is defined as the time from randomization to death from any cause | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Percentage of Participants Who Have Survived at 2 Years | 2-year landmark survival, defined as survival at 2 years | 2 years | 
| Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Scale Score | Time to deterioration in global health status/healthrelated quality of life (GHS/HRQoL), defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score | Time to deterioration in physical functioning, defined as the time from randomization to first observed ≥ 10-point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment. The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL. | Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months) | 
| Percentage of Participants With Adverse Events and Serious Adverse Events |  | Baseline up to 6 months after the last dose of study treatment (approximately 33 months) | 
| Serum Concentration of Atezolizumab |  | Pre-infusion Day 1 of Cycles 1-4; 30 minutes post-infusion Day 1 of Cycles 1 and 4; at Atezolizumab discontinuation (up to approximately 33 months)(1 Cycle = 28 days) | 
| Plasma Concentration of Cobimetinib Dose: 20/40 mg |  | Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) | 
| Plasma Concentration of Cobimetinib Dose: 60 mg |  | Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) | 
| Plasma Concentration of Vemurafenib |  | Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days) | 
| Percentage of Participants Positive for Anti-Drug Antibodies (ADA) to Atezolizumab | Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline | Pre-infusion Day 1 of Cycles 1-4; at Atezolizumab discontinuation (up to approximately 90 months)(1 Cycle=28 days) (approximately up to 33 months) |