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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
  Purpose

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.


Condition Intervention Phase
Myelodysplastic Syndrome
Chronic Myelomonocytic Leukemia (Dysplastic Type)
Acute Myeloid Leukemia With Multilineage Dysplasia
Drug: entinostat
Drug: azacitidine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.)


Enrollment: 197
Study Start Date: August 2006
Estimated Study Completion Date: April 2016
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Patients receive azacitidine (50 mg/m2) subcutaneously once daily on days 1-10 in a 28-day cycle.
Drug: azacitidine
Given subcutaneously
Other Names:
  • 5-AC
  • 5-AZA
  • 5-azacytidine
  • 5-azacitidine
  • Vidaza
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.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00313586

  Show 232 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Steven Gore, M.D. Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00313586     History of Changes
Other Study ID Numbers: NCI-2009-01077, NCI-2009-01077, E1905, U10CA021115
Study First Received: April 11, 2006
Results First Received: November 18, 2014
Last Updated: November 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
azacitidine
entinostat
myelodysplastic syndrome
chronic myelomonocytic leukemia
acute myeloid leukemia with multilineage dysplasia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Syndrome
Bone Marrow Diseases
Disease
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Neoplasms
Neoplasms by Histologic Type
Pathologic Processes
Precancerous Conditions
Azacitidine
Entinostat
Histone Deacetylase Inhibitors
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014