Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To compare the rates of complete remission (CR) plus CR with incomplete recovery (CRi) achieved with cytosine arabinoside (ara-C) (cytarabine) plus the checkpoint kinase 1 (CHK1) inhibitor MK-8776 (Chk1 inhibitor SCH 900776) vs. ara-C alone for adults (ages 18-75) with relapsed acute myelogenous leukemia (AML).

SECONDARY OBJECTIVES:

I. To evaluate and compare the toxicities of ara-C + MK-8776 vs. ara-C alone. II. To determine the disease free and overall survival of those achieving response to treatment.

III. To determine the impact of MK-8776 on AML blast cell deoxyribonucleic acid (DNA) repair protein expression profiles and correlate the expression profiles with CR/CRi in response to ara-C + MK-8776 vs. ara-C alone.

IV. To evaluate and compare the amount of DNA damage induced in AML blasts by ara-C + MK-8776 vs. ara-C.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cytarabine intravenously (IV) continuously over 72 hours on days 1-3 and 10-12 and Chk1 inhibitor SCH 900776 IV over 30 minutes on days 2, 3, 11, and 12.

ARM B: Patients receive cytarabine as in Arm A.

In both arms, courses may repeat every 28 days.

After completion of study treatment, patients are followed up periodically.

• Cytarabine (Drug), also known as CHX-3311, U-19920: Given IV
• CHK1 Inhibitor SCH 900776 (Drug), also known as SCH 900776: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies

Primary outcomes

• Response Rate(CR/CRi) Rate [Up to 3 years]: For descriptive purposes, the CR/CRi (complete response/Complete response with incomplete blood count recovery) rate will be reported at the end of the study separately for Arm A and Arm B. Responses are following definitions consistent with those published by Dohner H, Estey EH, Amadori S, et al. CR is defined as Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. CRi: All CR criteria except for residual neutropenia (ANC < 1000/μL)

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Adults with the established, pathologically confirmed diagnosis of relapsed AML
* AML that has relapsed at least once or is primary induction failure
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Patients must be able to give informed consent
* Female patients of childbearing age must have negative pregnancy test
* Serum creatinine =< 2.0 mg/dl
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x upper limit normal (ULN), unless due to Gilbert's, hemolysis or leukemic infiltration
* Alkaline phosphatase =< 5 x ULN, unless due to Gilbert's, hemolysis or leukemic infiltration
* Bilirubin =< 2.0 mg/dl, unless due to Gilbert's, hemolysis or leukemic infiltration
* Left ventricular ejection fraction >= 45% by multi gated acquisition scan (MUGA) or echocardiogram
* Baseline Fridericia corrected QT (QTcF) < 480 msec
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 30 days after study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are >= 4 weeks from stem cell infusion, have no active graft-vs-host disease (GVHD), and meet other eligibility criteria
* Patients who fail primary induction therapy or relapse after achieving complete remission (CR) are eligible if they have undergone no more than 2 prior cytotoxic regimens (a regimen is described as a distinctive planned collection of agent\[s\] and/or modalities to be utilized together during a cycle or course of therapy; i.e., induction+consolidation with or without stem cell transplant \[SCT\]), >= 2 weeks off cytotoxic chemotherapy, and >= 2 weeks off radiation therapy; patients must be off biologic therapies including hematopoietic growth factors >= 2 weeks; if using hydroxyurea (HU), steroids, imatinib or other tyrosine kinase inhibitors (TKIs), interferon, or other non-cytotoxics for blast count control, patient must be off for >= 24 hours (hrs) before starting MK-8776
* Fluvoxamine and ciprofloxacin must be stopped 7 days prior to day 1 of therapy, and be excluded during administration of study therapy; if the subject is using any of the other drugs that are cytochrome P4501A2 (CYP1A2) or P-glycoprotein (PgP) inhibitors, substitution should be considered and administration of these drugs should be avoided on the days of administration of MK-8776; in addition, smoking should be avoided and cytochrome P450 3A4 (CYP3A4) substrates with a narrow therapeutic index should be avoided: alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine

Exclusion Criteria:

* Any previous treatment with MK-8776
* Considered refractory or treatment failure to most recent treatment regimen, unless primary refractory
* Concomitant chemotherapy, radiation therapy, or immunotherapy
* Hyperleukocytosis with >= 50,000 blasts/uL (if using HU, steroids, tyrosine kinase/src inhibitors (including fms-related tyrosine kinase 3 \[FLT3\] inhibitors), arsenic, interferon or leukapheresis for blast count control, patient must be off those agents for 24 hours prior to beginning ara-C +/- MK-8776)
* Acute progranulocytic leukemia (APL, M3)
* Active disseminated intravascular coagulation (DIC)
* Active central nervous system (CNS) leukemia
* Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics are eligible
* Presence of other life-threatening illness
* Patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
* Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-8776
* History of Fridericia corrected QT (QTcF) prolongation greater than grade 1 or 480 msec
* Subjects with the following cardiac risk factors must be excluded: transmural myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack (TIA) or seizure disorder within 6 months prior to study drug administration
* Subjects with history of risk factors for torsades de pointes: clinical history of heart failure (New York Heart Association \[NYHA\] class III or IV), hypo- or hyper-kalemia or hypomagnesemia (supplementation to bring levels within normal limits prior to administration of MK-8776 is acceptable) or family history of Long QT Syndrome
* Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy or who have a prior history of acquired immunodeficiency syndrome (AIDS) indicator conditions, other than history of lymphoma more than 3 years remote

Participant flow

Outcome results

• Response Rate(CR/CRi) Rate (Primary), Number, participants: Arm A (Cytarabine, Chk1 Inhibitor SCH 900776) 6; Arm B (Cytarabine) 9

Adverse events

Serious adverse events by term

Other adverse events by term

6 more terms not shown.

• B. Smith, Principal investigator, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

NIH grants: U01CA070095, P30CA006973