Study of SCH 900776 (MK-8776) With and Without Cytarabine in Participants With Acute Leukemias (P05247)
Condition: Myelogenous Leukemia, Acute; Leukemia, Lymphocytic, Acute; Leukemia, Lymphoblastic, Acute, Philadelphia-Positive; Myelogenous Leukemia, Chronic, Aggressive Phase
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Myeloid, Accelerated Phase
Intervention: MK-8776; Cytarabine
Intervention description: IV infusion; IV infusion
Intervention MeSH terms: Cytarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study of SCH 900776 (MK-8776) will evaluate its safety and tolerability when given in
      combination with cytarabine to participants with acute leukemias. Participants in the
      Dose-Escalation Part will be enrolled in cohorts that will receive sequentially higher doses
      of MK-8776 in combination with standard doses of cytarabine. Only one combination treatment
      cycle of approximately 4 to 6 weeks is anticipated, but participants may receive additional
      cycles if clinically indicated after discussion between the Investigator and the Sponsor. The
      recommended combination doses for a Phase 2 trial (RP2D) will be determined based on safety
      and biological activity. Up to 10 to 15 additional participants will be studied at the
      combination RP2D.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have a histologically or cytologically confirmed diagnosis of relapsed and/or
             refractory acute leukemia, including:

               -  acute myelogenous leukemia (AML), including AML arising from myelodysplasia (MDS)
                  or myeloproliferative disorder (MPD);

               -  acute lymphocytic leukemia, including Philadelphia chromosome-positive (Ph+) ALL
                  (Dose-Escalation Part only);

               -  chronic myelogenous leukemia (CML) in accelerated phase (AP) or blast crisis (BC)
                  of either myeloid or lymphoid origin (Dose-Escalation Part only);

               -  treatment-related high-grade MDS (i.e. refractory anemia with excess blasts in
                  transformation [RAEBT]);

               -  MPD in transformation [eg, CMMoL-T (5%-19% blasts)].

          -  Must have recurred or progressed following standard therapy or failed standard
             therapy, or have disease for which no standard therapy currently exists.

          -  Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
             2.

          -  Females of childbearing potential must have a negative pregnancy test within 5 days
             prior to first dose of cytarabine.

          -  Females of childbearing potential and males whose sexual partner is 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
             treatment.

          -  Must have adequate renal function as evidenced by a serum creatinine level <=1.5 x
             upper limit of normal (ULN) or a calculated creatinine clearance >=60 mL/min.

          -  Participants, except ones with known Gilbert's Syndrome, must have adequate hepatic
             function as evidenced by a serum bilirubin level <=1.5 mg/dL AND serum levels of
             aspartate and alanine aminotransferase (AST/ALT) <=5 x the ULN for the reference
             laboratory.

          -  Must have adequate cardiac function with a left ventricular ejection fraction (LVEF)
             of >=45% (echocardiogram or multiple-gated acquisition [MUGA] scan).

          -  Must be recovered from the effects of any prior surgery, radiotherapy, or systemic
             antineoplastic therapy.

          -  Participants who are refractory to or relapsed after prior allogeneic or autologous
             stem cell transplant are eligible.

        Exclusion Criteria:

          -  Must not have known hypersensitivity to MK-8776 or cytarabine or to any of their
             excipients or have received therapy with another Checkpoint kinase 1 (CHK1) inhibitor.

          -  Must not have persistent, unresolved Common Terminology Criteria for Adverse Events
             version 3.0 (CTCAE v 3.0) ≥ Grade 2 drug-related toxicity (except alopecia, erectile
             impotence, hot flashes, decreased libido, hematologic toxicity) associated with
             previous treatment.

          -  Must not have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C, or
             have a known history of liver cirrhosis or active alcohol abuse.

          -  Must not be New York Heart Association (NYHA) Class III (has marked limitation in
             activity due to symptoms, even during less than ordinary activity [e.g. walking short
             distances >20-100 m]; is comfortable only at rest) or Class IV (has severe
             limitations; experiences symptoms even while at rest; mostly bed bound).

          -  Must not have undergone major surgery within 3 weeks prior to first study drug
             administration after enrollment.

          -  Must not have known active central nervous system (CNS) or leptomeningeal leukemia.

          -  Must not have received radiation therapy within 2 weeks prior to first study treatment
             administration after enrollment or radiation therapy to >25% of bone marrow.

          -  Must not have received more than 4 prior induction regimens.

          -  Must not have a peripheral blast count ≥50,000/mm^3.

          -  Must not have active, uncontrolled graft versus host disease (GVHD) post-allogeneic
             stem cell transplant.

          -  Must not have had any of the following within 6 months prior to first study treatment
             administration after enrollment: myocardial infarction, severe/unstable angina
             pectoris, coronary/peripheral artery bypass graft, symptomatic congestive heart
             failure, cerebrovascular accident or transient ischemic attack, or seizure disorder.

          -  Must not have a known bleeding diathesis, e.g. hemophilia, or disseminated
             intravascular coagulation.

          -  Must not have an active, uncontrolled infection.

          -  Must not have a history of cytarabine-related neurotoxicity.

          -  Must not have a baseline corrected QT (QTc) interval >470 msec (i.e. CTCAE v 3.0 Grade
             ≥2).

          -  Must not currently be a smoker and/or must not be likely to smoke during the study.

          -  Females must not be breast-feeding, pregnant, or intend to become pregnant.