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.

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