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

Phase 2

Completed

• Conditions: Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Minimal Differentiation
• Interventions: Drug: Cytarabine; Drug: CHK1 Inhibitor SCH 900776; Other: Laboratory Biomarker Analysis

• Registration Number: NCT01870596
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This randomized phase II trial studies how well cytarabine with or without SCH 900776 works in treating adult patients with relapsed acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. SCH 900776 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cytarabine is more effective with or without SCH 900776 in treating acute myeloid leukemia.

Detailed Description

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.

Study Timeline

• Study Start: 2013-05
• Study First Submitted: 2013-06-03
• Study First Submitted QC: 2013-06-03
• Study First Posted: 2013-06-06
• Primary Completion: 2014-12
• Study Completion: 2014-12
• Results First Submitted: 2015-09-11
• Status Verified: 2016-07
• Results First Submitted QC: 2016-07-20
• Last Update Submitted: 2016-07-20
• Results First Posted: 2016-09-01
• Last Update Posted: 2016-09-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (cytarabine, Chk1 inhibitor SCH 900776)	CHK1 Inhibitor SCH 900776	Patients receive cytarabine 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 A (cytarabine, Chk1 inhibitor SCH 900776)	Laboratory Biomarker Analysis	Patients receive cytarabine 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 (cytarabine)	Laboratory Biomarker Analysis	Patients receive cytarabine as in Arm A.
Arm A (cytarabine, Chk1 inhibitor SCH 900776)	Cytarabine	Patients receive cytarabine 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 (cytarabine)	Cytarabine	Patients receive cytarabine as in Arm A.

Primary Outcome Measures

Name	Time	Method
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)

Trial Locations

Locations (5)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Blood and Marrow Transplant Group of Georgia; 🇺🇸 Atlanta, Georgia, United States

Mayo Clinic in Arizona; 🇺🇸 Scottsdale, Arizona, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States