E6201 and Dabrafenib for the Treatment of Central Nervous System Metastases From BRAF V600 Mutated Metastatic Melanoma

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose of MEK-1/MEKK-1 inhibitor E6201 (E6201) in combination with dabrafenib in patients with central nervous system (CNS) metastases from BRAF V600- mutated metastatic melanoma. (Phase I) II. To assess the response rates treated at the maximum tolerated dose of E6201 in combination with dabrafenib in patients with central nervous system (CNS) metastases from BRAF V600- mutated metastatic melanoma. (maximum tolerated dose \[MTD\] + Expansion Cohort) SECONDARY OBJECTIVES: I. To assess the time to first progression in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib. II. To assess overall survival (OS) in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib. III. To assess the adverse events profile of E6201 in combination with dabrafenib in subjects with CNS metastases due to metastatic melanoma with a BRAF V600 mutation treated with E6201 + dabrafenib. CORRELATIVE RESEARCH OBJECTIVE: I. To assess the impact of BRAF mutational status (e.g., type, heterozygosity or homozygosity) in archival tissue with clinical outcome. OUTLINE: This is a dose-escalation study of MEK-1/MEKK-1 inhibitor E6201 followed by a dose-expansion study. Patients receive MEK-1/MEKK-1 inhibitor E6201 intravenously (IV) over 2 hours on days 1, 4, 8, 11, 15, and 18, and dabrafenib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, computed tomography (CT) or magnetic resonance imaging (MRI) throughout study. After completion of study treatment, patients are followed up every 6 months for up to 2 years from time of registration.