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:

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