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

This is a Phase 1 study of E6201 plus dabrafenib for the treatment of CNS metastases in BRAF V600-mutated metastatic melanoma. A total of up to N=28-34 subjects with melanoma metastasized to the CNS will be included.

Selected subjects will be: both males and females age ≥18 years; histologically confirmed melanoma with BRAF V600 mutation with CNS metastasis; archived tumor sample from the primary, recurrent or metastatic disease with documented BRAF mutation; recovered from all acute toxicities (≤ Grade 1) due to prior immunotherapy; determined to have adequate renal and hepatic function, and no known history of significant cardiac disease.

Monotherapy Safety Run-in Phase: Following screening, a total of up to 4 subjects were enrolled. E6201 was administered by intravenous (IV) infusion over a 2-hour period at a dose of 320 mg/m\^2 twice weekly (Days 1, 4, 8, 11, 15 and 18) for three weeks, repeated every 28 days (1 cycle) until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.

Combination Safety Run-in Phase: Following screening, a total of 6-12 subjects are anticipated to establish the recommended doses of E6201 plus dabrafenib. E6201 will be administered by IV infusion over a 2-hour period twice weekly (Days 1, 4, 8, 11, 15 and 18) repeated every 28 days plus dabrafenib orally twice daily (=1 cycle).

Dose Level 1: E6201 320 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -1: E6201 240 mg/m\^2 twice weekly plus dabrafenib 150 mg BID. Dose Level -2: E6201 240 mg/m\^2 twice weekly plus dabrafenib 100 mg BID. Dose Level -3: E6201 160 mg/m\^2 twice weekly plus dabrafenib 100 mg BID Dose Level -4: E6201 160 mg/m\^2 twice weekly plus dabrafenib 75 mg BID. Dose Level -5: E6201 160 mg/m\^2 twice weekly plus dabrafenib 50 mg BID.

A total of 6 subjects will be treated at the combined MTD doses for both drugs in the Combination Safety Run-in Phase before beginning the Expansion Phase.

Expansion Phase: An additional cohort of up to N=18 subjects will be treated at the E6201 plus dabrafenib combined MTD. Subjects treated at the MTD in the Combination Safety Run-in Phase will count towards accrual in the Expansion Phase.

CNS disease response will be assessed according to 2 methodologies: Response Evaluation Criteria in Solid Tumors (RECIST v. 1.1) and Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM). Non-CNS systemic disease will be assessed according to RECIST v. 1.1.

Blood for hematology and serum chemistry determinations will be collected and ECGs will be taken during the study. Assessments will be obtained at Week 8 and every 8 weeks thereafter until documented progression of disease (PD). Subjects who demonstrate clinical benefit will be allowed to continue therapy with E6201 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.

Eligibility Criteria:
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

Exclusion Criteria:

* Urgent need of treatment to prevent acute neurologic deterioration, including urgent neurosurgery or radiotherapy
* Symptoms of uncontrolled intracranial pressure
* Symptomatic or untreated spinal cord compression
* Prior treatment with any chemotherapeutic or investigational agent
* Prior treatment with any BRAF and/or MEK inhibitor for metastatic disease
* Prior treatment with \> 1 line of immunotherapy for metastatic disease
* Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV
* QT interval corrected for rate (QTc) \> 480 msec for on the ECG obtained at Screening using Fridericia method for QTc calculation
* Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring systemic antiviral treatment within the last week prior to study treatment
* Other active infection requiring IV antibiotic usage within the last week prior to study treatment
* Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results
* Pregnant or breast-feeding