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

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

Safety Run-in Phase: Following screening, a total of up to 6 subjects will be enrolled. E6201
will be 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.Dose
reductions for toxicity will be 240 mg/m^2 twice weekly (Dose Level -1) and 160 mg/m^2 twice
weekly (Dose Level -2), administered over the same schedule as above, Days 1, 4, 8, 11, 15
and 18 for three weeks, repeated every 28 days.

Once 6 subjects are treated in the Safety Run-in Phase and an MTD is confirmed (e.g.,
starting dose level, Dose Level -1 or Dose Level -2), the Expansion Phase will be initiated.

Expansion Phase: An additional cohort of up to N=18 subjects will be treated at the MTD.
Subjects treated at the MTD in the 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.

Inclusion Criteria:

- Males and females ≥ 18 years of age

- Histologically or cytologically confirmed BRAF- or MEK-mutated melanoma

- BRAF- or MEK-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

- Documented metastasis of the primary tumor to the CNS and not a candidate for surgical
intervention nor require immediate radiation therapy to relieve symptoms

- Other metastatic melanoma systemic disease allowed

- Minimum intervals required to be off treatment prior to Cycle 1 Day 1:

- Prior radiotherapy (RT) to current field of CNS disease ≥ 4 weeks

- Nitrosourea cytotoxic drug ≥ 6 weeks

- Non-nitrosourea cytotoxic drug or any systemic investigational agent with
exception of methotrexate ≥ 4 weeks

- Approved PD-1/PD-L1 inhibitors, CTLA4 checkpoint inhibitors, or other
immunotherapy ≥ 4 weeks

- Approved BRAF and MEK inhibitors ≥ 3 weeks

- Methotrexate or non-BRAF/MEK non-cytotoxic anti-tumor drug ≥ 2 weeks

- Radiographically measurable disease in the CNS documented ≤ 3 weeks prior to starting
E6201 treatment

- Asymptomatic or symptomatic CNS metastasis allowed

- Previously-treated or untreated CNS metastasis 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

- Prior treatment with 1 BRAF inhibitor and/or 1 MEK inhibitor allowed

- 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

- Evidence of leptomeningeal metastases

- Symptomatic or untreated spinal cord compression

- 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

- Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface
antigen (HBsAg) or hepatitis C virus (HCV)

- 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