Clinical Trials /

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

NCT03332589

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS)
  • Official Title: A Phase 1 Study of E6201 Plus Dabrafenib for the Treatment of Central Nervous System Metastases (CNS) From BRAF V600-Mutated Metastatic Melanoma

Clinical Trial IDs

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

Conditions

  • Malignant Melanoma
  • Brain Metastases

Interventions

DrugSynonymsArms
E6201Monotherapy Safety Run-in: E6201
E6201 plus dabrafenibCombination Safety Run-in: E6201 Plus Dabrafenib

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Monotherapy Safety Run-in: E6201ExperimentalE6201 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
Combination Safety Run-in: E6201 Plus DabrafenibExperimentalDose 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.
  • E6201 plus dabrafenib
Expansion: E6201 Plus DabrafenibExperimentalA total of up to N=18 will be treated at the E6201 plus dabrafenib combined MTD.
  • E6201 plus dabrafenib

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 metastais, 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
      
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 V600 mutation
  • E6201
  • Dabrafenib

Last Updated

April 29, 2020