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
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 corrected QT (QTc) < 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 (induction + consolidation or induction + SCT are considered each as 1
regimen), >= 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
- 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 QTc 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