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