An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor

Inclusion Criteria

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Patients must have histologically or cytologically confirmed Stage IV or recurrent or unresectable Stage III melanoma.
• BRAF mutation-positive melanoma (i.e., V600E, V600K or V600D)
• For Cohort A, patients must have easily accessible tumor for a mandatory biopsy. This is not required for patients enrolled on Cohort B.
• Patients must have measurable disease, defined by RECIST 1.1
• Patients must have tumor lesions which is refractory or resistant to a selective BRAF inhibitor (RO5185426 or GSK2118436).
• Age >/= 16 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have organ and marrow function as defined below: · absolute neutrophil count >/= 1,500/mcL · platelets >/= 75,000/mcL · total bilirubin /= 60 mL/min/1.73 m2 for patients with creatinine levels above 1.3 X institutional upper limit of normal.
• Ability to understand and the willingness to sign a written informed consent document.
• For Cohort B, patients must have at least 1 measureable parenchymal brain metastasis of at least 10 mm in the greatest diameter and no greater than 40 mm diameter. There must be at least one parenchymal brain metastasis that has not received any previous locally-directed treatment (i.e. surgery or radiation), or that has progressed after prior treatment for the brain metastases (i.e. surgery or radiation).
• Male subjects must agree to use contraception, this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication. However, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm).
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol /= 480 msec (>/= 500 msec for subjects with Bundle Branch Block).
• Uncontrolled arrhythmias. • Subjects with controlled atrial fibrillation for >1 month prior to study Day 1 are eligible.
• Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study if deemed not clinically significant)
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients. NOTE: To date there are no known FDA approved drugs chemically related to GSK2118436 or GSK1120212.
• Pregnant or lactating female.
• Unwillingness or inability to follow the procedures required in the protocol.
• Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity
• Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency.