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

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: 1. 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) 2. immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy) 3. 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: 1. ANC \> 1500/µL 2. Platelets ≥ 100,000/µL 3. 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: 1. St. John's wort or hyperforin 2. 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: 1. Current unstable angina 2. Current symptomatic congestive heart failure of NYHA class 2 or higher 3. History of congenital long QT syndrome or mean QTcF \> 450 msec at baseline or uncorrectable electrolyte abnormalities 4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible) 5. Left ventricular ejection fraction (LVEF) below 50% 6. Uncontrolled Arrhythmias 7. Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months