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Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00313586
First received: April 11, 2006
Last updated: November 18, 2014
Last verified: April 2014

April 11, 2006
November 18, 2014
August 2006
July 2013   (final data collection date for primary outcome measure)
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. ] [ Designated as safety issue: No ]

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.)
Not Provided
Complete list of historical versions of study NCT00313586 on ClinicalTrials.gov Archive Site
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Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia
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

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. Both treatment-induced and non-treatment-induced cohorts are allowed. 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.

PRIMARY OBJECTIVES:

I. To estimate the response rate (complete, partial, and trilineage response) in both treatment arms for the two cohorts

SECONDARY OBJECTIVES:

I. Evaluate the toxicity of azacitidine and entinostat in 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. Two groups of patients, treatment-induced cohort and non-treatment-induced cohort, are enrolled on this study. Patients are stratified 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). Both cohorts are randomized to 1 of 2 treatment arms.

ARM A: Patients receive azacitidine subcutaneously once daily on days 1-10.

ARM B: Patients receive azacitidine as in arm A 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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia (Dysplastic Type)
  • Acute Myeloid Leukemia With Multilineage Dysplasia
  • Drug: entinostat
    Given orally
    Other Names:
    • MS-27-275
    • MS-275
    • SNDX-275
  • Drug: azacitidine
    Given subcutaneously
    Other Names:
    • 5-AC
    • 5-AZA
    • 5-azacytidine
    • 5-azacitidine
    • Vidaza
  • Experimental: Arm A
    Patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle.
    Intervention: Drug: azacitidine
  • Experimental: Arm B
    Patients receive azacitidine as in arm A and oral entinostat (4 mg/m2) on days 3 and 10 of each 28-day cycle.
    Interventions:
    • Drug: entinostat
    • Drug: azacitidine
Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, Herman J, Juckett M, Smith MR, Malick L, Paietta E, Czader M, Litzow M, Gabrilove J, Erba HP, Gore SD, Tallman MS. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J Clin Oncol. 2014 Apr 20;32(12):1242-8. doi: 10.1200/JCO.2013.50.3102. Epub 2014 Mar 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
197
April 2016
July 2013   (final data collection date for primary outcome measure)

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 (CMMoL; dysplastic subtype)

      • White blood cells (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 French-American-British (FAB) criteria allowed
      • AML-TLD by World Health Organization (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
  • Therapy-induced MDS, AML-TLD, or chronic myelomonocytic leukemia (dysplastic subtype) allowed
  • Age ≥ 18 years.
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • ECOG performance status 0-2
  • Creatinine < 2.0 mg/dL
  • Bilirubin normal (unless due to intramedullary or extramedullary hemolysis, or Gilbert's syndrome)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal
  • Life expectancy ≥ 6 months
  • SWOG (Southwest Oncology Group) patients must be enrolled in research study trial SWOG-9007

Exclusion Criteria:

  • Pregnant or nursing
  • Prior treatment with azacitidine, decitabine or entinostat
  • Active infections
  • Prior induction chemotherapy for AML or stem cell transplantation
  • Clinical evidence of central nervous system (CNS) or pulmonary leukostasis or disseminated intravascular coagulation or CNS leukemia
  • Serious or uncontrolled medical conditions
  • Advanced malignant hepatic tumors
  • Known hypersensitivity to azacitidine or mannitol
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00313586
NCI-2009-01077, NCI-2009-01077, E1905, U10CA021115
No
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Study Chair: Steven Gore, M.D. Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP