Clinical Trials /

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

NCT03332589

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: E6201 for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)
  • Official Title: A Phase 1 Study of E6201 for the Treatment of Central Nervous System Metastases (CNS) From BRAF or MEK-Mutated Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: STX-101-02
  • NCT ID: NCT03332589

Conditions

  • Malignant Melanoma
  • Brain Metastases

Interventions

DrugSynonymsArms
E6201E6201 320 mg/m^2 IV twice weekly

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
E6201 320 mg/m^2 IV twice weeklyExperimentalE6201 320 mg/m^2 administered IV over 2 hours twice weekly on Days 1, 4, 8, 11, 15 and 18, repeated every 28 days (=1 cycle). Dose reductions for toxicity are 240 mg/m^2 (Dose Level -1) and 160 mg/m^2 (Dose Level -2) twice weekly.
  • E6201

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Intracranial disease overall response rate by RANO-BM
Time Frame:At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days)
Safety Issue:
Description:CNS disease response will be assessed by Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM)

Secondary Outcome Measures

Measure:Intracranial disease duration of response
Time Frame:At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days)
Safety Issue:
Description:Length of time from the first evidence of objective response to the first evidence of progression
Measure:Systemic disease overall response rate (other than in the CNS)
Time Frame:At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days)
Safety Issue:
Description:Systemic disease response will be assessed by RECIST 1.1.
Measure:Progression-Free Survival
Time Frame:From Cycle 1 Day 1 through 6 months following the last dose of study drug (each cycle is 28 days)
Safety Issue:
Description:Length of time from the date of first administration of study drug to the first evidence of disease progression or death, whichever is earlier
Measure:Overall Survival
Time Frame:From Cycle 1 Day 1 through 6 months following the last dose of study drug or death, whichever is earlier (each cycle is 28 days)
Safety Issue:
Description:Length of time from the date of first administration of study drug to the date of death from any cause
Measure:Safety of E6201 in this patient population
Time Frame:From Cycle 1 Day 1 through 6 months following the last dose of study drug or death, whichever is earlier (each cycle is 28 days)
Safety Issue:
Description:Safety assessed through the monitoring of adverse events (AEs) and serious adverse events (SAEs).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Spirita Oncology, LLC

Trial Keywords

  • Melanoma
  • CNS metastases
  • BRAF mutation
  • MEK mutation
  • E6201

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