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