Clinical Trials /

A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations

NCT02418000

Description:

This is a Phase 1/2a dose-escalation study of E6201, a dual mitogen-activated protein kinase/extracellular-signal regulated kinase 1 (MEK1) and FMS-like tyrosine kinase 3 (FLT3) inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 and/or rat sarcoma (Ras) mutations. The Phase1 portion of the study will be a safety run-in (up to 30 subjects) to establish a recommended Phase 2 dose (RP2D). The Ph. 2a portion of the study will evaluate three specific patients groups: Cohort 1 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor; Cohort 2 will enroll patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor; Cohort 3 will enroll patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation
  • Official Title: A Phase 1/2a Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation, Including Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (CMML)

Clinical Trial IDs

  • ORG STUDY ID: BSC-101-01
  • NCT ID: NCT02418000

Conditions

  • AML
  • MDS
  • CMML

Interventions

DrugSynonymsArms
E6201novel inhibitor of FMS-like tyrosine kinase-3 (FLT3)Lowest dose of E6201 weekly

Purpose

This is a Phase 1/2a dose-escalation study of E6201, a dual MEK1 and FLT3 inhibitor, in subjects with advanced hematologic malignancies with documented FLT3 mutation. The Phase1 portion of the study will be a safety run-in (up to 30 subjects) to establish a recommended Phase 2 dose (RP2D). The Ph. 2a portion of the study will evaluate two specific patients groups: Cohort 1 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3 inhibitor while Cohort 2 will enroll up to 26 patients with relapsed or refractory AML and confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3 inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a confirmed Ras mutation and no FLT3 mutation. Cohorts 1 and 2 of the expansion phase will incorporate a Simon 2-stage optimal design. A total of up to N=92 subjects will be enrolled in the study.

Detailed Description

      Phase 1 (Safety Run-In): Following Screening, a total of up to 30 subjects in up to 5 dose
      cohorts will be enrolled to establish the RP2D. The safety run-in phase will be a standard
      3+3 cohort design.

      Phase 2a (Expansion): Once the Phase 1 Safety Run-In portion of the study is complete and an
      RP2D is established, additional subjects will be enrolled into the Phase 2 Expansion portion
      in three cohorts. Cohort 1 will enroll up to 26 patients with relapsed or refractory AML and
      confirmed FLT3 mutation (with or without a Ras mutation) without prior exposure to a FLT3
      inhibitor. Cohort 2 will enroll up to 26 patients with relapsed or refractory AML and
      confirmed FLT3 mutation (with or without a Ras mutation) with prior exposure to a FLT3
      inhibitor. Cohort 3 will enroll up to 10 patients with relapsed or refractory AML with a
      confirmed Ras mutation and no FLT3 mutation. Cohort 1 and 2 of the Expansion Phase will
      incorporate a Simon 2-stage optimal design. Subjects with AML enrolled in the Phase 1 portion
      of the study at the RP2D will count towards the Phase 2a accrual for the appropriate cohort.

      Subjects will receive E6201 weekly or bi-weekly on a 28-day schedule, with the schedule and
      dose level established in the safety run-in portion of the study. Disease assessments,
      including analysis of blood and bone marrow aspirates, will be performed at the end of Cycles
      1 and 3 and every 2 cycles thereafter. Disease assessments may be made at other time points
      at the discretion of the Investigator.

      Subjects who demonstrate objective response will be allowed to continue therapy with E6201
      until progression of disease, observation of unacceptable adverse events, intercurrent
      illness or changes in the patient's condition that prevents further study participation.

      ECGs will be performed during the study. Blood will be also collected during the study for
      hematology, serum chemistry, pharmacokinetics and pharmacodynamics assessments. Bone marrow
      will be collected for the assessment of disease response and mutational status.
    

Trial Arms

NameTypeDescriptionInterventions
Lowest dose of E6201 weeklyExperimentalLowest dose of E6201 administered as an IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle)
  • E6201
Highest dose of E6201 weeklyExperimentalHighest dose of E6201 administered as an IV over 2 hours once weekly, on Days 1, 8, 15, and 22, repeated every 28 days (= 1 cycle)
  • E6201
Lowest dose of E6201 twice weeklyExperimentalLowest dose of E6201 administered as an IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22 and 25, repeated every 28 days (= 1 cycle)
  • E6201
Highest dose of E6201 twice weeklyExperimentalHighest dose of E6201 administered as an IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 22 and 25, repeated every 28 days (= 1 cycle)
  • E6201
Mid dose of E6201 twice weeklyExperimentalMid dose of E6201 administered as an IV over 2 hours twice weekly, on Days 1, 4, 8, 11, 15, 18, 22, 25, repeated every 28 days (= 1 cycle)
  • E6201

Eligibility Criteria

        Inclusion Criteria:

        Phase 1 and 2: Confirmed advanced hematologic malignancies

          -  Confirmed relapsed or refractory AML with a documented FLT3 mutation, or

               -  60 years with newly diagnosed FLT3+ AML and not eligible for standard induction
                  chemotherapy or FLT3+

          -  high-risk MDS/CMML (defined as ≥ 10% peripheral blood or marrow blasts and
             international Prognostic Scoring System [IPSS] score ≥ 2) and relapsed or refractory
             to prior therapy

          -  At least 3 weeks beyond the last cancer treatment for the disease under study, major
             surgery and recovered from all acute toxicities (≤ Grade 1). Hydroxyurea used to
             control peripheral blast counts is permitted during the first 2 cycles.

          -  Adequate performance status ECOG ≤ 2;

          -  Adequate renal and hepatic function:

               -  creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance ≥ 45 mL/minute

               -  total bilirubin ≤ 2 times the upper limit of normal (ULN) unless due to Gilbert's
                  disease or thought to be due to underlying AML

               -  ALT and AST ≤ 5 times ULN

          -  Negative serum pregnancy test within 14 days prior to the first dose of study therapy
             for women of child-bearing potential

          -  Ability to provide written informed consent

        Exclusion Criteria:

          -  History of clinically significant cardiac impairment, congestive heart failure (CHF)
             New York Heart Association (NYHA) Class III or IV, unstable angina, or myocardial
             infarction during the previous 6 months, or serious cardiac arrhythmia

          -  QT interval corrected for rate (QTc) ≥ 450 msec for males and ≥ 460 msec for females
             on the ECG obtained at Screening using Fridericia method for QTc calculation (average
             of 3 readings)

          -  Concomitant medication(s) that may cause QTc prolongation or induce Torsades de
             Pointes with the exception of anti-microbials used as standard of care to prevent or
             treat infections and other such drugs that are considered by the investigator to be
             essential for the care of the patient. However, if such medications are deemed to be
             necessary during the study, E6201 will be held during the period of their use. of
             anti-microbials used as standard

          -  Presence of active central nervous system (CNS) leukemia. Subjects adequately treated
             for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples negative for
             leukemia cells are eligible. Subjects with no history of CNS leukemia will not be
             required to undergo cerebrospinal fluid sampling for eligibility.

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

          -  Active, uncontrolled infection

          -  Known hypersensitivity to any study drug component

          -  History of another malignancy; Exception: Patients disease-free for 2 years or treated
             in situ carcinoma

          -  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

          -  Pregnancy or lactation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)
Time Frame:12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Determination of overall response rate
Time Frame:Response and survival assessed at end of C1 and every 2 cycles thereafter through 6 months following last dose of study drug
Safety Issue:
Description:Response criteria by IWG Response Criteria for AML or IWG Response Criteria for MDS and CMML subjects
Measure:Evaluate the pharmacokinetics profile of E6201 in plasma will be determined (Cmax, Tmax, Half-life, AUC, Clearance, Volume of Distribution)
Time Frame:Cycle 1 Days 1 and 15, Cycle 2 Day 1
Safety Issue:
Description:Cmax, Tmax, Half-life, AUC, Clearance, Volume of Distribution
Measure:Levels of phospho-FMS-like tyrosine kinase-3 (pFLT3) will be measured in blood and bone marrow samples
Time Frame:Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1
Safety Issue:
Description:Changes from baseline in PD parameters for each cohort

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Strategia Therapeutics

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