Milademetan Plus Quizartinib Combination Study in FLT3-ITD Mutant Acute Myeloid Leukemia (AML)
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Quizartinib; Milademetan; Milademetan
Intervention description: 20 or 30 mg tablets for oral administration; 5, 20, 80 or 200 mg capsules for oral administration; 5, 20, 80 or 200 mg capsules for oral administration; 30, 45, 80, or 100 mg capsules may be utilized
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Part 1 Single Group 1 Arm, Part 2 Parallel, 2 Cohorts
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Relapsed/Refractory; Newly Diagnosed; Unfit for Chemotherapy; Positive for FLT3-ITD Mutation

Summary:

      Participants with AML that have gone into remission and come back (relapsed) or gone into
      remission with a number of leukemia cells still in their system (refractory) will be
      recruited for this study. They will also be positive for FLT3-ITD mutation.

      Participants will receive a combined dose of quizartinib and milademetan that have not been
      approved by the US Food and Drug Administration yet (m).

      The combination of these drugs will be provided in different amounts on defined days (dosing
      schedules).

      It is expected that the combination of milademetan and quizartinib will be safe and well
      tolerated. It is expected that the combination may fight the leukemia better than a single
      drug.

      The study will run for approximately 3 years. There may be up to 156 participants.

      The study has 2 parts:

        -  Part 1 will test 24-36 participants in approximately 15 study centers globally.
           Participants will receive two study drugs (milademetan and quizartinib) in different
           amounts on specific days. Information will be gathered to see what dosing schedule of
           the drug combination is best (maximum tolerated/recommended dose).

        -  Part 2 of the study will confirm the recommended dosing schedule identified in Part 1 is
           effective. A larger number of participants will receive the recommended dose in
           approximately 15 additional sites worldwide as necessary, based on the enrollment rate,
           the population, and the standard of care available to them at the time of enrollment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has reached ≥18 years old or the age of the age of majority in their country

          -  Part 1 (dose escalation): Has FLT3-ITD mutant (≥ 3% FLT3-ITD/total FLT3) AML (primary
             AML, secondary, or therapy-related AML), and has treatment failure to prior AML
             therapy or have relapsed after prior AML therapy

          -  Part 2 (dose expansion): Has FLT3-ITD mutant (≥3% FLT3-ITD/total FLT3) AML (primary,
             secondary, or therapy-related AML), and has treatment failure to prior AML therapy or
             have relapsed after prior AML therapy, OR has newly diagnosed AML who are ineligible
             for intensive induction chemotherapy

          -  Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (or 3 for
             patients with newly diagnosed AML between 18 and 74 years old)

          -  Has protocol-defined adequate renal, hepatic and cardiac status

          -  Is not pregnant, and if not postmenopausal or a surgically sterile male or female, is
             willing to use a highly effective contraceptive method upon enrollment, during the
             course of the study, and for 6 months following the last dose of investigational drug

          -  Is able and willing to provide protocol-defined bone marrow biopsies/aspirates

        Exclusion Criteria:

          -  Has central nervous system (CNS) involvement of leukemia - patients with a history of
             CNS leukemia may be eligible if the CNS leukemia is adequately controlled (defined as
             no clinical symptoms of CNS disease and at least 2 consecutive lumbar punctures with
             no evidence of disease prior to study enrollment) after discussion and approval from
             the Sponsor

          -  Has acute promyelocytic leukemia (AML subtype M3)

          -  Has uncontrolled or significant cardiovascular disease or QTc interval >450 ms
             (average of triplicate determination)

          -  Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or
             antifungals.

          -  Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C
             infection based on positive tests during Screening

          -  Has persistent, clinically significant > Grade 1 non-hematologic toxicity from prior
             AML therapies

          -  Has any history or medical condition, metastatic condition, drug/medication use or
             other condition that might, per protocol or in the opinion of the investigator,
             compromise:

               1. safety or well-being of the participant or offspring

               2. safety of study staff

               3. analysis of results