Patient case: 13-year-old male with acute myeloid leukemia; genetic feature: FLT3

Clinical trial: A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 Mutation

Summary: 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.

Eligibility: 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

Relevance to patient case: not relevant