Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.

Official Title
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Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases

Conditions
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Active Melanoma Brain Metastases

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 Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory At least one measurable intracranial target lesion for which all of the following criteria are met: previously untreated or progressive according to RECIST 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (SRS and/or craniotomy) immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy) largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not allowed ECOG PS 0-2 Life expectancy >12 weeks Age 18 years or older Adequate bone marrow function as indicated by the following: ANC > 1500/µL Platelets ≥ 100,000/µL Hemoglobin > 9 g/dL Adequate renal function, as indicated by creatinine =/< 1.5 x the upper limit of normal (ULN) Adequate liver function, as indicated by bilirubin =/< 1.5 x ULN AST or ALT < 3 x ULN (patients with documented liver metastases: AST and/or ALT =/< 5 x ULN) Able to swallow pills Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Exclusion Criteria: Active infection Prior therapy with BRAFi and/or MEKi Leptomeningeal disease Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. Symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed Current use of therapeutic warfarin Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia Conditions that will interfere significantly with the absorption of drugs Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast allergy Pregnant, lactating, or breast feeding women Prior radiation therapy within the last 14 days Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix Unwillingness or inability to comply with study and follow-up procedures The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: St. John's wort or hyperforin Grapefruit juice History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, Retinal Vein Occlusion (RVO), or neovascular macular degeneration Uncontrolled glaucoma with intra-ocular pressures > 21mmHg Serum cholesterol ≥ Grade 2 Hypertriglyceridemia ≥ Grade 2 Hyperglycemia (fasting) ≥ Grade 2 History of clinically significant cardiac dysfunction, including the following: Current unstable angina Current symptomatic congestive heart failure of NYHA class 2 or higher History of congenital long QT syndrome or mean QTcF > 450 msec at baseline or uncorrectable electrolyte abnormalities Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible) Left ventricular ejection fraction (LVEF) below 50% Uncontrolled Arrhythmias Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cobimetinib in Combination with Vemurafenib<br>Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water. Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water. | Drug: Cobimetinib<br>* 60mg once a day; will be taken on days 1-21 of each 28 day treatment cycle; will be taken in combination with Vemurafenib;<br>Drug: Vemurafenib<br>* 960mg twice a day; 28 day treatment cycle; will be taken in combination with Cobimetinib;<br>* Other names: Zelboraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Intracranial Response (OIRR) | Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients. | Until disease progression, less than or equal to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response | Response to study treatment achieved by individual patients as indicated by an overall change in size of the sum of diameters from baseline of up to 5 intracranial target lesions and up to 5 extracranial target lesions. | Until disease progression, less than or equal to 5 years. | 
| Progression-free Survival (PFS) | Time (number of months) from first documented evidence of overall Complete Response (CR) or Partial Response (PR) until time of first documented disease progression or death due to any cause (for individual patients). Progression as defined by RECIST 1.1 (Response Evaluation Criteria In Solid Tumors) is a ≥ 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g. percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm. | Up to 5 years | 
| Overall Survival (OS) | Number of months of survival for individual patients. | Up to 5 years | 
| Duration of Response | Change in relative apparent diffusion coefficient (rADC) as measured by MRI as early predictor of response value/result for each patient | Until disease progression, less than or equal to 5 years. | 
| Immune Modulation in Peripheral Blood |  | Up to 5 years | 
| Early Markers of Progression in Peripheral Blood |  | Up to 5 years | 
| Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br) | The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is used to measure general quality of life (QOL) that reflects symptoms or problems associated with brain malignancies across 5 scales. The brain subscale is usually used along with the core (general) questionnaire that includes 27 items. The measure yields information about total QOL, as well as information about the dimensions of physical well-being, social/family well-being, emotional well being, functional well-being, and disease-specific concerns. Patients rate all 5 items using a five-point Likert scale ranging from 0 not at all to 4 very much. Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items). Scoring range is 0-200. | Up to 5 years |