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

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Brief Title

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

Official Title

Randomized Phase II Trial of Timed Sequential Cytosine Arabinoside (Ara-C) With and Without the Checkpoint Kinase 1 (CHK1) Inhibitor MK-8776 in Adults With Relapsed AML

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Response Rate(CR/CRi) Rate


Condition

Adult Acute Megakaryoblastic Leukemia

Intervention

Cytarabine

Study Arms / Comparison Groups

 Arm A (cytarabine, Chk1 inhibitor SCH 900776)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

32

Start Date

May 2013

Completion Date

December 2014

Primary Completion Date

December 2014

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

B. Smith, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01870596

Organization ID

NCI-2013-01097

Secondary IDs

NCI-2013-01097

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

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


Verification Date

July 2016