Study of MK-8242 Alone and in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia (P07649)
Condition: Acute Myelogenous Leukemia (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: MK-8242
Intervention description: MK-8242 capsules, orally, once per day on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7) up to a maximum of 12 cycles. Starting dose will be 30 mg and will be escalated in successive cohorts until maximum tolerated dose (MTD) is established. Beginning at a dose level of ≥120 mg total daily dose (TDD), the dosing regimen will switch to twice daily (BID). Amendment 4 added a 21-day dosing cycle in which MK-8242 would be given BID on Days 1-7 of each cycle, at the assigned dose level.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a study of MK-8242 alone and in combination with cytarabine in adult participants
      with refractory or recurrent acute myelogenous leukemia (AML). The study will have 2 Arms.
      Arm A is for participants with refractory or recurrent AML who are considered ineligible for
      standard chemotherapy. In Part 1 of Arm A, participants will receive MK-8242 monotherapy in
      escalating doses to determine the recommended phase 2 dose [RP2D]. In Part 2, participants
      will receive monotherapy with MK-8242 to confirm the RP2D and assess preliminary efficacy.
      Arm B is for participants with recurrent AML following an initial complete remission (CR) or
      CR with incomplete marrow recovery (CRi) of 6 to 12 months duration. In Part 1 of Arm B,
      participants will receive MK-8242 in escalating doses + cytarabine to determine the RP2D in
      combination with cytarabine. In Part 2, participants will receive MK-8242 + cytarabine to
      confirm the RP2D and assess preliminary efficacy. The pharmacokinetics of MK-8242 will be
      studied in both arms. With Amendment 4 (22 August 2013) a 21-day dosing cycle is added, with
      MK-8242 being given on Days 1-7 of each 21-day cycle in both the monotherapy and combination
      therapy arms; data from Arm A will be used to determine whether a participant receives 21-day
      or 28-day therapy in Arm B.
    

Eligibility criteria:

        Inclusion criteria:

          -  For Arm A Part 1 (monotherapy/dose escalation): refractory or recurrent AML, not an
             appropriate candidate for standard therapy

          -  For Arm A Part 2 (monotherapy/dose confirmation/cohort expansion): refractory or
             recurrent AML, not an appropriate candidate for standard therapy, and have wild type
             p53 gene mutation analysis

          -  For Arm B Part 1 (combination therapy/dose escalation): recurrent AML having achieved
             an initial CR or CRi of 6-12 months duration and age ≥18 years old and <70 years old

          -  For Arm B Part 2 (combination therapy/dose confirmation/cohort expansion): recurrent
             AML having achieved an initial CR or CRi of 6-12 months duration, age ≥18 years old
             and <70 years old, and have wild type P53 gene mutation analysis

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 for all Arm
             A, or 0 or 1 for all Arm B

          -  Negative pregnancy test within 72 hours of the first dose of study medication

          -  Female participants and male participants and their partners who are of childbearing
             potential must agree to abstain from sexual intercourse or to use an acceptable method
             of contraception during the study and for 90 days following the last dose of study
             therapy

          -  Adequate organ function

          -  Recovered from the effects of any prior surgery, radiotherapy or anti-neoplastic
             treatment, with the exception of alopecia

          -  Must be able to swallow, retain, and absorb oral medications and oral nutrition

          -  Must follow the appropriate washout period for prohibited treatments

        Exclusion criteria:

          -  Active malignancy other than AML

          -  Leptomeningeal leukemia requiring intrathecal therapy

          -  For Arm A and B, Part 1 only: history of myelodysplastic syndrome (MDS)

          -  For Arm A and B, Part 2: AML in the background of MDS may be included

          -  Isolated extramedullary leukemia without also meeting bone marrow criteria for acute
             leukemia

          -  AML blast crisis of chronic myelogenous leukemia (CML)

          -  Bone marrow transplant with active graft-versus host disease (GVHD) or who receives
             immunosuppressive therapy

          -  Uncontrolled active infection that requires systemic treatment

          -  Clinically significant hepatitis at Screening, or hepatitis C antibody positive,
             hepatitis B surface antigen positive, or human immunodeficiency virus (HIV)
             seropositive

          -  Persistent, unresolved, drug-related toxicity

          -  Breast-feeding, pregnant, intends to become pregnant or intends to breast feed during
             the study or has a positive pregnancy test at Screening

          -  A person participating in any other clinical study with a potentially therapeutic
             agent or who has received another investigational product within 5 half-lives (if the
             half-life is known) or 28 days (if the half-life is unknown) prior to Day 1 of cycle 1

          -  A participant who, within the past 6 months, has had any of the following: myocardial
             infarction, coronary/peripheral artery bypass graft, cerebrovascular accident,
             transient ischemic attack, or uncontrolled seizure disorder (i.e., seizures within the
             past 6 months)

          -  A participant who, at the time of Screening, presents with: unstable or uncontrolled
             angina, New York Heart Association (NYHA) class III or IV congestive heart failure,
             uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically
             significant electrocardiogram (ECG) abnormality

          -  Known bleeding disorder, e.g. hemophilia or disseminated intravascular coagulopathy or
             on anti-coagulation therapy

          -  For Arm B only: Known hypersensitivity to cytarabine