- Compare the overall response rate (complete, partial, and hematologic improvement-major by International Working Group [IWG] criteria) in patients with treatment-induced or non-treatment-induced myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (dysplastic), or acute myeloid leukemia with multilineage dysplasia treated with azacitidine with vs without entinostat.
- Compare the major response rate (complete and partial responses by IWG criteria) in patients treated with these regimens.
- Evaluate the toxicity of azacitidine and entinostatin these patients.
- Identify changes in gene promoter methylation and gene expression that may be associated with response to azacitidine and entinostat.
- Identify other molecular mechanisms (such as DNA damage) that may be associated with response to azacitidine and entinostat.
OUTLINE: This is a randomized, multicenter study. Patients are first stratified according to treatment-related disease (yes vs no), followed by a second stratification according to disease (myelodysplastic syndromes [MDS] high/intermediate-2 vs MDS low/intermediate-1 vs chronic myelomonocytic leukemia vs acute myeloid leukemia with multilineage dysplasia). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive azacitidine subcutaneously once daily on days 1-10.
- Arm II: Patients receive azacitidine as in arm I and oral entinostat on days 3 and 10.
Treatment in both arms repeats every 28 days for at least 6 and up to 24 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed periodically for 5 years.
PROJECTED ACCRUAL: A total of 196 patients will be accrued for this study.
- Bone marrow aspirate and/or biopsy-confirmed diagnosis of 1 of the following:
- Myelodysplastic syndromes (MDS)
- Any International Prognostic Score (IPSS) eligible
- Patients with low or intermediate-1 IPSS must have platelet count < 50,000/mm³ and/or absolute neutrophil count < 500/mm³
- Blast count < 20%
- Chronic myelomonocytic leukemia (dysplastic subtype)
- WBC < 12,000/mm³ (measured twice within the past 4 weeks, 2 weeks apart)
- Acute myeloid leukemia with multilineage dysplasia (AML-TLD)
- Formerly diagnosed refractory anemia with excess blasts in transformation by FAB criteria allowed
- AML-TLD by WHO criteria allowed in patients with no history of antecedent hematologic disorder
- WBC ≤ 30,000/mm³ (measured twice within the past 4 weeks, 2 weeks apart)
- WBC that has doubled over 4 weeks AND > 20,000/mm³ is not eligible
- Evidence of ≥ 20% blasts on review of the bone marrow aspirate and/or biopsy
- SWOG patients must be enrolled in research study trial SWOG-9007
- Therapy-induced MDS, AML-TLD, or chronic myelomonocytic leukemia (dysplastic subtype) allowed
- No clinical evidence of CNS or pulmonary leukostasis or disseminated intravascular coagulation
- No clinical evidence of CNS leukemia
- See Disease Characteristics
- ECOG performance status 0-2
- Life expectancy ≥ 6 months
- Creatinine < 2.0 mg/dL
- Bilirubin normal (unless due to intramedullary or extramedullary hemolysis, or Gilbert's syndrome)
- AST and ALT ≤ 2.5 times upper limit of normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No active infections
- No advanced malignant hepatic tumors
- No other serious or uncontrolled medical conditions
- No known hypersensitivity to azacitidine or mannitol
PRIOR CONCURRENT THERAPY:
- Recovered from prior therapy
- No prior azacitidine, decitabine or entinostat
- No prior induction chemotherapy for AML or stem cell transplantation
- No hematopoietic growth factors within 3 weeks prior to study entry
- No other concurrent investigational or commercial agents or therapies for the malignancy
- No concurrent valproic acid, epoetin alfa, or darbepoetin alfa
- No filgrastim (G-CSF) or pegfilgrastim during days 1-10 of each treatment course
Last updated: 05/18/2012
NCT ID: NCT00313586