Trial of Vemurafenib and Cobimetinib in Patients With Advanced BRAFV600 Mutant Melanoma

Study Overview
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Brief Summary
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This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma.

Official Title
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An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Cobimetinib
* Drug: Vemurafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Signed HIV testing consent Life expectancy ≥ 12 weeks Able to swallow pills ECOG performance status 2 or less Adequate bone marrow function Adequate renal function Adequate liver function Negative urine pregnancy test within 7 days prior to commencement of dosing in premenopausal women Histological diagnosis of unresectable AJCC stage III or stage IV, BRAFV600E/K mutant melanoma Measurable disease Accessible tumor that can be biopsied Naive to targeted therapy (Prior immune-based therapy in the adjuvant setting or for advanced disease will be allowed if >2 weeks from study entry) Exclusion Criteria: Active systemic infection Active autoimmune disease or history of known or suspected autoimmune disease Active brain metastases or leptomeningeal metastases Treatment with any immunomodulatory medication within 4 weeks of initiation of study therapy. Positive test for hepatitis B virus Positive test for hepatitis C virus Positive test for human immunodeficiency virus (HIV) Pregnant, lactating or breast feeding women Localized radiation therapy within the last 14 days History of malabsorption No consumption of the following within 7 days prior to start of treatment: St. John's wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor History or evidence of cardiovascular risk History or evidence of retinal pathology

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1<br>Ten patients begin Vemurafenib monotherapy, after 10 days, begin combination therapy by adding Cobimetinib. | Drug: Cobimetinib<br>* A potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway.<br>* Other names: GDC-0973, XL518;Drug: Vemurafenib<br>* A low molecular weight, orally available inhibitor of the activated form of the BRAF serine-threonine kinase enzyme, which is commonly found in melanoma<br>* Other names: RO5185426, PLX4032, or RG7204;|
| Active Comparator: Cohort 2<br>Ten patients begin Cobimetinib monotherapy, after 10 days, begin combination therapy by adding Vemurafenib. | Drug: Cobimetinib<br>* A potent and highly selective inhibitor of MEK1 and MEK2, central components of the RAS/RAF pathway.<br>* Other names: GDC-0973, XL518;Drug: Vemurafenib<br>* A low molecular weight, orally available inhibitor of the activated form of the BRAF serine-threonine kinase enzyme, which is commonly found in melanoma<br>* Other names: RO5185426, PLX4032, or RG7204;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma. | compare immunologic changes described above with the development of study treatment-related adverse events. For example, severity or extent of rash from cobimetinib (a well-described dermatologic toxicity of MEK inhibitors) may be compared to levels of intratumoral immune activation assessed by one or more of the parameters. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma. | compare immunologic changes described above with therapeutic outcomes, including CR, PR, SD, and PD measured by RECIST 1.1. For example, tumor regression may be correlated with levels of intratumoral immune activation or expression of immune checkpoints assessed by one or more of the parameters | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, Vemurafenib, Cobimetinib