Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial is studying azacitidine and 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 or by stopping them from dividing. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may kill more cancer cells

Further Study Information

PRIMARY OBJECTIVES:

I. 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.

II. Compare the major response rate (complete and partial responses by IWG criteria) in patients treated with these regimens.

SECONDARY OBJECTIVES:

I. Evaluate the toxicity of azacitidine and entinostatin these patients. II. Identify changes in gene promoter methylation and gene expression that may be associated with response to azacitidine and entinostat.

III. 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.

Eligibility Criteria

Inclusion Criteria:

• 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

• No filgrastim (G-CSF) or pegfilgrastim during days 1-10 of each treatment course

• 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

• 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

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Steven Gore

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00313586
Information obtained from ClinicalTrials.gov on March 19, 2013

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