Study of SCH 900776 (MK-8776) With and Without Cytarabine in Participants With Acute Leukemias (P05247)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Dose-Escalation Study of SCH 900776 in Combination With Cytarabine in Subjects With Acute Leukemias (Protocol No. P05247)

Conditions
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Myelogenous Leukemia, Acute, Leukemia, Lymphocytic, Acute, Leukemia, Lymphoblastic, Acute, Philadelphia-Positive, Myelogenous Leukemia, Chronic, Aggressive Phase

Intervention / Treatment
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* Drug: MK-8776
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8776 10 mg/m^2 + Cytarabine 2 g/m^2<br>Participants received MK-8776 10 mg/m^2 intravenously (IV) on Days 2 and 3 and again on Days 11 and 12 PLUS cytarabine 2 g/m^2 IV via 72-hour continuous intravenous infusion (CIV) on Days 1 through 3 and repeated on Days 10 through 12 of a treatment cycle. The duration of one treatment cycle was to be approximately 4 to 6 weeks (until hospital discharge). | Drug: MK-8776<br>* IV infusion<br>* Other names: SCH 900776;Drug: Cytarabine<br>* IV infusion<br>* Other names: Cytosar-U®;|
| Experimental: MK-8776 20 mg/m^2 + Cytarabine 2 g/m^2<br>Participants received MK-8776 20 mg/m^2 IV on Days 2 and 3 and again on Days 11 and 12 PLUS cytarabine 2 g/m^2 IV via 72-hour CIV on Days 1 through 3 and repeated on Days 10 through 12 of a treatment cycle. The duration of one treatment cycle was to be approximately 4 to 6 weeks (until hospital discharge). | Drug: MK-8776<br>* IV infusion<br>* Other names: SCH 900776;Drug: Cytarabine<br>* IV infusion<br>* Other names: Cytosar-U®;|
| Experimental: MK-8776 40 mg/m^2 + Cytarabine 2 g/m^2<br>Participants received MK-8776 40 mg/m^2 IV on Days 2 and 3 and again on Days 11 and 12 PLUS cytarabine 2 g/m^2 IV via 72-hour CIV on Days 1 through 3 and repeated on Days 10 through 12 of a treatment cycle. The duration of one treatment cycle was to be approximately 4 to 6 weeks (until hospital discharge). | Drug: MK-8776<br>* IV infusion<br>* Other names: SCH 900776;Drug: Cytarabine<br>* IV infusion<br>* Other names: Cytosar-U®;|
| Experimental: MK-8776 56 mg/m^2 + Cytarabine 2 g/m^2<br>Participants received MK-8776 56 mg/m^2 IV on Days 2 and 3 and again on Days 11 and 12 PLUS cytarabine 2 g/m^2 IV via 72-hour CIV on Days 1 through 3 and repeated on Days 10 through 12 of a treatment cycle. The duration of one treatment cycle was to be approximately 4 to 6 weeks (until hospital discharge). | Drug: MK-8776<br>* IV infusion<br>* Other names: SCH 900776;Drug: Cytarabine<br>* IV infusion<br>* Other names: Cytosar-U®;|
| Experimental: MK-8776 140 mg + Cytarabine 2 g/m^2<br>Participants received MK-8776 140 mg flat dose IV on Days 2 and 3 and again on Days 11 and 12 PLUS cytarabine 2 g/m^2 IV via 72-hour CIV on Days 1 through 3 and repeated on Days 10 through 12 of a treatment cycle. The duration of one treatment cycle was to be approximately 4 to 6 weeks (until hospital discharge). | Drug: MK-8776<br>* IV infusion<br>* Other names: SCH 900776;Drug: Cytarabine<br>* IV infusion<br>* Other names: Cytosar-U®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | Toxicity was assessed according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v 3.0). DLTs in Cycle 1 consisted of any of the following: 1) Selected Grade 4 drug-related nonhematologic toxicities, 2) Selected Grade 3 drug-related nonhematologic toxicities that do not resolve to ≤ Grade 2 within 48 hours: Neurotoxicity of any duration, Nephrotoxicity of any duration, QT interval corrected by Fridericia (QTcF) prolongation of any duration, 3) Inability to administer Day 10 cytarabine therapy due to ongoing, uncontrolled serious or life-threatening toxicity. The number of participants who experienced a DLT during Cycle 1 is summarized. | Throughout Cycle 1 (Up to 6 weeks) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to this study treatment. The number of participants who experienced an AE is summarized. | Up to 45 days after last dose of study treatment (Up to 180 days) | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to this study treatment. The number of participants who discontinued study treatment due to an AE is summarized. | Up to 135 days |