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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


Phase 2
18 Years
75 Years
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Recurrent Adult Acute Myeloid Leukemia

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Trial Information

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


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 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.

III. 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 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete response (CR/CRi) rate

Outcome Description:

For descriptive purposes, the CR/CRi rate will be reported at the end of the study separately for Arm A and Arm B with exact binomial 95% confidence intervals. The final analysis will be by an exact Cochrane-Mantel-Haenszel test, which tests for an overall treatment difference while adjusting for disease subgroup. The primary analysis will conclude a significant benefit for Arm A over Arm B if the one-sided p value is less than 0.10.

Outcome Time Frame:

Up to 3 years

Safety Issue:

No

Principal Investigator

B. Smith

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-01097

NCT ID:

NCT01870596

Start Date:

May 2013

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Recurrent Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins HospitalBaltimore, Maryland  21231