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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

Phase 2
18 Years
Open (Enrolling)
Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Untreated Adult Acute Myeloid Leukemia

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Trial Information

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


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.


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.

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

- SWOG patients must be enrolled in research study trial SWOG-9007

- Therapy-induced MDS, AML-TLD, or chronic myelomonocytic leukemia (dysplastic subtype)

- No clinical evidence of CNS or pulmonary leukostasis or disseminated intravascular

- 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

- No concurrent valproic acid, epoetin alfa, or darbepoetin alfa

Type of Study:


Study Design:

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

Outcome Measure:

The complete response rate, partial response rate, and trilineage response rate

Outcome Description:

Graded according to standard international response criteria.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Steven Gore

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

August 2006

Completion Date:

Related Keywords:

  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Untreated Adult Acute Myeloid Leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute



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Emory University Atlanta, Georgia  30322
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Ottawa Regional Hospital and Healthcare Center Ottawa, Illinois  61350
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Medical Oncology and Hematology Associates-West Des Moines Clive, Iowa  50325
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Mercy Medical Center - Des Moines Des Moines, Iowa  50314
Medical Oncology and Hematology Associates-Des Moines Des Moines, Iowa  50309
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University of Missouri - Ellis Fischel Columbia, Missouri  65203
Veterans Administration Columbia, Missouri  65201
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University of Tennessee - Knoxville Knoxville, Tennessee  37920
Saint Paul Hospital Dallas, Texas  75235
Medical Consultants Limited Milwaukee, Wisconsin  53215
University of Minnesota Medical Center-Fairview Minneapolis, Minnesota  55455
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Stanford University Hospitals and Clinics Stanford, California  94305
Siouxland Hematology Oncology Associates Sioux City, Iowa  51101
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Illinois Cancer Specialists-Niles Niles, Illinois  60714
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