A Randomized Phase II Trial of Azacitidine With or Without the Histone Deacetylase Inhibitor Entinostat for the Treatment of Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia (Dysplastic Type), and Acute Myeloid Leukemia With Multilineage Dysplasia
Overview
- Phase
- Phase 2
- Intervention
- Azacitidine
- Conditions
- Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 197
- Locations
- 234
- Primary Endpoint
- Proportion of Patients With Clinical Response
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This randomized phase II trial studies azacitidine with or without entinostat to see how well they work compared to azacitidine alone in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may work better in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the overall response rate (complete, partial, and hematologic improvement-major by International Working Group \[IWG\] criteria) in response to azacitidine and entinostat. II. To estimate the major response rate (complete and partial responses by the IWG response criteria) to a 10-day regimen of azacitidine and to the same regimen of azacitidine in combination with entinostat administered orally on days 3 and 10 of each cycle in patients with de novo myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMMoL) (dysplastic) and acute myeloid leukemia with trilineage dysplasia (AML-TLD), as well as in patients with treatment-induced MDS, CMMoL (dysplastic) and AML-TLD. SECONDARY OBJECTIVES: I. To evaluate the toxicity of azacitidine and entinostat in this patient population. II. To identify changes in gene promoter methylation and gene expression which may be associated with response to azacitidine and entinostat. III. To identify other molecular mechanisms (such as deoxyribonucleic acid \[DNA\] damage) which may be associated with response to azacitidine and entinostat. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-10. ARM B: Patients receive azacitidine as in Arm A and entinostat orally (PO) on days 3 and 10. In both arms, treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The following diagnoses will be eligible for this study:
- •Myelodysplastic syndromes: the diagnosis of MDS must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; NOTE: blast count must be \< 20%; patients with any International Prognostic Score (IPSS) are eligible; patients with low or intermediate (INT)-1 IPSS must have a platelet count \< 50,000/mm\^3 and/or absolute neutrophil count (ANC) \< 500/mm\^3 within seven days prior to registration
- •Chronic myelomonocytic leukemia (dysplastic subtype): the diagnosis of CMMoL must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; patients with CMMoL must have a WBC \< 12,000/mm\^3, documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken)
- •Acute myeloid leukemia with multilineage dysplasia: the diagnosis of AML-TLD must be confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to registration; NOTE: there must be evidence of \>= 20% blasts on the review of the bone marrow aspirate and/or biopsy; AML-TLD will be interpreted to include patients formerly diagnosed by French-American-British (FAB) criteria as refractory anemia with excess blasts in transformation (RAEB-t), as well as patients with no history of antecedent hematologic disorder who have AML which meets criteria for AML-TLD by World Health Organization (WHO) criteria; patients with AML-TLD must have a white blood cell (WBC) =\< 30,000/mm\^3 documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken); patients whose WBC has doubled within this period of time and is greater than 20,000/mm\^3 at the time of screening will not be eligible
- •Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within two weeks prior to registration to rule out pregnancy
- •Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception
- •Patient must have Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
- •Patient must have no prior treatment with azacitidine, decitabine or entinostat
- •Patients must not have active infections at the time of registration
- •Serum creatinine \< 2.0 mg/dL; test must be done within seven days prior to registration
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (azacitidine)
Patients receive azacitidine SC QD on days 1-10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm A (azacitidine)
Patients receive azacitidine SC QD on days 1-10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm B (azacitidine, entinostat)
Patients receive azacitidine as in Arm A and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm B (azacitidine, entinostat)
Patients receive azacitidine as in Arm A and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Entinostat
Arm B (azacitidine, entinostat)
Patients receive azacitidine as in Arm A and entinostat PO on days 3 and 10. Treatment repeats every 28 days for 6-24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
Proportion of Patients With Clinical Response
Time Frame: Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2 - 5 years from study entry.
Clinical response is defined as a complete response (CR), partial response (PR) or trilineage response (TR) graded according to the following criteria: 1. World Health Organization classification of the acute leukemias and myelodysplastic syndrome (by Bennett) 2. Myelodysplastic syndromes standardized response criteria: further definition (by Cheson et al.) 3. Report of an international working group to standardize response criteria for myelodysplastic syndromes (by Cheson et al.)