E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)

Inclusion Criteria

• •Males and females ≥ 18 years of age
• •Histologically or cytologically confirmed BRAFV600-mutated melanoma
• •Documented metastasis of the primary tumor to the CNS
• •BRAF-mutation melanoma tumor status will be established prior to entry based on previous BRAF-gene analysis or MEK pathway mutation reports from a CLIA qualified laboratory. If a report is not available, the mutation analysis will be performed at Screening on archival tissue
• •Other metastatic melanoma systemic disease allowed
• •At least one measurable brain metastasis, 0.5 - 3.0 cm, as assessed by MRI ≤ 3 weeks prior to initiation of study treatment, provided neurological sequelae have resolved completely and at least one measurable metastasis with documented disease progression is present on MRI
• •Prior stereotactic radiosurgery and/or excision of up to 3 brain metastases is allowed \> 3 weeks before initiation of study treatment, provided neurological sequelae have resolved completely and at least one measurable metastasis with documented disease progression is present on MRI
• •One prior line of immunotherapy for metastatic disease is allowed, if ≥ 2 weeks has elapsed between the end of therapy and initiation of study treatment
• •Prior melanoma adjuvant immunotherapy is allowed, if ≥ 6 months has elapsed between the end of therapy and initiation of study treatment
• •Prior melanoma adjuvant BRAF/MEK inhibitor therapy is allowed, if ≥ 12 months has elapsed between the end of therapy and initiation of study treatment
• •Able to swallow and retain oral medication with no clinically significant gastrointestinal abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels (Combination Safety Run-in and Expansion Phases of the study only)
• •Asymptomatic or symptomatic CNS metastasis is allowed
• •Stable dose of corticosteroids for CNS metastasis for ≥ 7 days allowed
• •Patients with seizures due to CNS metastases must be controlled with stable anti-epileptic treatment for ≥ 14 days
• •Bisphosphonates and/or denosumab are allowed
• •Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2
• •Life expectancy of ≥ 3 months
• •Adequate hematologic parameters without ongoing transfusional support:
• •* Hemoglobin (Hb) ≥ 9 g/dL
• •* Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9 cells/L
• •* Platelets ≥ 75 x 10\^9 cells/L
• •Adequate renal and hepatic function:
• •* Creatinine ≤ 1.5 x the upper limit of normal (ULN), or calculated creatinine clearance ≥ 50 mL/minute x 1.73 m\^2
• •* Total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's disease
• •* ALT/AST ≤ 2.5 times ULN, or \< 5 times ULN for subjects with liver metastases
• •Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after the completion of study treatment.
• •Ability to provide written informed consent