Patient case: 51-year-old female with papillary thyroid carcinoma; genetic feature: BRAF (V600E)

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

Summary: This is a Phase 1 study of E6201 for the treatment of CNS metastases in BRAF or MEK-mutated metastatic melanoma. A total of up to N=24 subjects with melanoma metastasized to the CNS will be included.

Detailed description: 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.

Eligibility: 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

Relevance to patient case: not relevant