Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia
Primary Purpose
Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cytarabine
CHK1 Inhibitor SCH 900776
Laboratory Biomarker Analysis
Sponsored by
About this trial
This is an interventional treatment trial for Adult Acute Megakaryoblastic Leukemia
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
Sites / Locations
- Mayo Clinic in Arizona
- Blood and Marrow Transplant Group of Georgia
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
- Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
- Mayo Clinic
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Arm A (cytarabine, Chk1 inhibitor SCH 900776)
Arm B (cytarabine)
Arm 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.
Patients receive cytarabine as in Arm A.
Outcomes
Primary Outcome Measures
Response Rate(CR/CRi) Rate
For descriptive purposes, the CR/CRi (complete response/Complete response with incomplete blood count recovery) rate will be reported at the end of the study separately for Arm A and Arm B. Responses are following definitions consistent with those published by Dohner H, Estey EH, Amadori S, et al. CR is defined as Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. CRi: All CR criteria except for residual neutropenia (ANC < 1000/μL)
Secondary Outcome Measures
Full Information
NCT ID
NCT01870596
First Posted
June 3, 2013
Last Updated
July 20, 2016
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01870596
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2016
Overall Recruitment Status
Completed
Study Start Date
May 2013 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Megakaryoblastic Leukemia, Adult Acute Monoblastic Leukemia, Adult Acute Monocytic Leukemia, Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With Maturation, Adult Acute Myeloid Leukemia With Minimal Differentiation, Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11, Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1, Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL, Adult Acute Myeloid Leukemia Without Maturation, Adult Acute Myelomonocytic Leukemia, Adult Erythroleukemia, Adult Pure Erythroid Leukemia, Alkylating Agent-Related Acute Myeloid Leukemia, Recurrent Adult Acute Myeloid Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
32 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A (cytarabine, Chk1 inhibitor SCH 900776)
Arm Type
Experimental
Arm 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.
Arm Title
Arm B (cytarabine)
Arm Type
Active Comparator
Arm Description
Patients receive cytarabine as in Arm A.
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
CHX-3311, U-19920
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
CHK1 Inhibitor SCH 900776
Other Intervention Name(s)
SCH 900776
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Response Rate(CR/CRi) Rate
Description
For descriptive purposes, the CR/CRi (complete response/Complete response with incomplete blood count recovery) rate will be reported at the end of the study separately for Arm A and Arm B. Responses are following definitions consistent with those published by Dohner H, Estey EH, Amadori S, et al. CR is defined as Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/μL and a platelet count of 100,000/μL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. CRi: All CR criteria except for residual neutropenia (ANC < 1000/μL)
Time Frame
Up to 3 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
B. Smith
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Blood and Marrow Transplant Group of Georgia
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia
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