
    closed due to slow accrual
  
['active melanoma brain metastases']
['cobimetinib', 'vemurafenib']

        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
      