A Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.

Official Title
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A Phase II Two Cohort Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases

Conditions
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Metastatic Melanoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease-specific inclusion criteria: Histologically confirmed melanoma with radiologically confirmed brain metastases Documented BRAFV600 mutation status of melanoma tumour tissue using a validated genetic test. Measurable brain metastases Prior systemic therapy for metastatic melanoma is allowed with exceptions as detailed in the exclusion criteria Prior SRT or surgical therapy of ≤ 10 brain metastases is allowed but prior WBRT is not allowed Adverse effects of all prior systemic or local treatment must have either returned to baseline or become stable and manageable prior to initiation of study treatment. General inclusion criteria: Age ≥18 years Able to comply with the study protocol, in the investigator's judgment ECOG Performance Status ≤ 2 Life expectancy of > 3 months Willing and able to complete health and quality of life questionnaires required by the protocol Adequate hematologic and end-organ function Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use two effective forms of contraception during the course of this study and for at least six months after completion of study therapy. Male patients must agree to refrain from donating sperm for at least six months after the last dose of cobimetinib Exclusion criteria: Disease-specific exclusion criteria: Ocular melanoma Leptomeningeal involvement Uncontrolled tumour-related pain Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days. Prior WBRT treatment for CNS disease Increasing corticosteroid dose during the seven days prior to initiation of study treatment or current dexamethasone or equivalent dose of > 8 mg/day Prior treatment with a BRAF or MEK inhibitor For patients assigned to Cohort 1 only: prior immunotherapy in the metastatic setting is not allowed. Prior immunotherapy is allowed in the adjuvant setting, provided it is completed ≥ 90 days prior to study treatment initiation. For patients assigned to Cohort 2 only: prior immunotherapy in either the adjuvant or metastatic setting is not allowed. Major surgical procedure other than for diagnosis within four weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or to any formulation component of cobimetinib or atezolizumab or, for patients assigned to Cohort 2 only, vemurafenib Any anti-cancer therapy, including chemotherapy, hormonal therapy and radiotherapy, within two weeks prior to initiation of study treatment Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants other than gabapentin, vigabatrin and levetiracetam Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days prior to initiation of study treatment unless the patient has an absolute contraindication to the to the use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin Active malignancy (other than melanoma) or a prior malignancy within the past three years General exclusion criteria: Known risk factors for ocular toxicity History of clinically significant cardiac dysfunction Inability to swallow medications Malabsorption condition that would alter the absorption of orally administered medications Traumatic injury within two weeks prior to initiation of study treatment Prior allogeneic stem cell or solid organ transplantation Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan Uncontrolled diabetes or symptomatic hyperglycaemia Any Grade ≥ 3 haemorrhage or bleeding event within 28 days of study treatment initiation History of stroke, reversible ischemic neurological defect, or transient ischemic attack within six months prior to study treatment initiation Positive human immunodeficiency virus (HIV) test at screening Hepatitis B virus (HBV) infection (chronic or acute) Active hepatitis C virus (HCV) infection Active tuberculosis History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins Severe infection within four weeks prior to initiation of study treatment Signs or symptoms of infection within two weeks prior to initiation of study treatment Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in, and completion of, the study Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up after treatment discontinuation Pregnancy, breastfeeding, or intention of becoming pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within seven days prior to initiation of study treatment. Treatment with therapeutic oral or IV antibiotics within two weeks prior to initiation of study treatment Administration of a live, attenuated vaccine within four weeks prior to initiationof study treatment or anticipation of need for such a vaccine during the study Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug, whichever is shorter, prior to study treatment initiation Treatment with systemic immunosuppressive medications within two weeks prior to study treatment initiation Treatment with investigational drug within 28 days or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment For patients to be assigned to Cohort 2 only: anticipated use of any concomitant medication during or within seven days prior to initiation of study treatment that is known to cause QT prolongation Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least seven days 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1- cobimetinib and atezolizumab<br>Participants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1-21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle. | Drug: Cobimetinib<br>* 60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle.<br>* Other names: Cotellic;Drug: Atezolizumab<br>* Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1).<br>* Other names: Tecentriq;|
| Experimental: Cohort 2 - cobimetinib, atezolizumab and vemurafenib<br>Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen. | Drug: Cobimetinib<br>* 60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle.<br>* Other names: Cotellic;Drug: Atezolizumab<br>* Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1).<br>* Other names: Tecentriq;Drug: Vemurafenib<br>* Participants will receive vemurafenib 960 mg (four 240 mg tablets) orally (PO) twice daily (BID) on days 1-21 of the run-in period (cycle 1); thereafter, they will receive vemurafenib 720 mg dose (three 240 mg tablets) PO BID on days 22-28 of cycle 1 and on days 1-28 of all subsequent cycles.<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial Objective Response Rate (ORR) | Intracranial ORR is defined as the proportion of patients with either a complete response (CR) or a partial response (PR) in their intracranial disease based on two consecutive assessments ≥ 4 weeks apart. Disease status for this endpoint will be determined by an Independent Review Committee (IRC) in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) with modified measurability definition for intracranial lesions (≥ 0.5 cm by MRI) and allowing up to five intracranial target lesions. CR is defined as disappearance of all lesions. PR is defined as ≥30% decrease in tumor burden, in the absence of CR. | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extracranial ORR | Extracranial ORR, defined as the proportion of patients with either a CR or PR in their extracranial disease based on two consecutive assessments ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. | Up to 48 months | 
| Overall ORR | Overall ORR, defined as the proportion of patients with either a CR or PR in their overall disease (i.e. including intracranial and extracranial disease) based on two consecutive assessments ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. | Up to 48 months | 
| Progression-Free Survival (PFS) | Intracranial, extracranial and overall PFS defined as the time from study treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1. | Up to 48 months | 
| Duration of Response (DOR) | Intracranial, extracranial and overall DOR, defined as the time from the first occurrence of a documented objective response based on two consecutive assessments ≥ 4 weeks apart to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. | Up to 48 months | 
| Disease Control Rate (DCR) | Intracranial, extracranial and overall DCR, defined as the proportion of patients with a CR or PR or stable disease (SD) at 16 weeks from study treatment initiation, as determined by the investigator according to RECIST v1.1. SD is defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for disease progression. Disease progression is defined as ≥20% increase in tumor burden. | Up to 48 months | 
| Overall Survival (OS) | OS is defined as the time from study treatment initiation to death from any cause. | Up to 48 months | 
| Time to cognitive symptom deterioration | Time from study treatment initiation to cognitive symptom deterioration, defined as a change (≥ 10 points on a 0-100 scale) on selected scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-BN20) (visual disorder, motor dysfunction, communication deficit, headaches, seizures and drowsiness). | Up to 48 months | 
| Time to symptom and function deterioration | Time from study treatment initiation to symptom and function deterioration defined as a change (≥ 10 points on a 0-100 scale) in fatigue, physical functioning, cognitive functioning, or role functioning as measured by the Fatigue, Physical, Cognitive, Role Functioning scales of the EORTC QLQ-C30. | Up to 48 months | 
| Duration of Stable/Improved Health-related Quality of Life (HRQoL) scores | Duration of Stable/Improved HRQoL scores as assessed through use of the two-item Global Health Status (GHS)/HRQoL subscale (Questions 29 and 30) of the EORTC QLQ-C30. | Up to 48 months | 
| Occurrence and Severity of Adverse Events | The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of occurrence and severity of AEs. Severity will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0) | Up to 48 months | 
| Number of participants reporting change from baseline in targeted vital signs | The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of number of participants reporting change from baseline in targeted vital signs e.g. ECG and blood pressure. | Up to 48 months | 
| Number of participants reporting change from baseline in targeted lab values. | The safety profile of Cobimetinib plus Atezolizumab and Cobimetinib plus Atezolizumab plus Vemurafenib is evaluated in terms of umber of participants reporting change from baseline in targeted lab values. | Up to 48 months |