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: October 25, 2013
Last verified: October 2013
  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. 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
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
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:
  • The complete response rate, partial response rate, and trilineage response rate [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Graded according to standard international response criteria.


Secondary Outcome Measures:
  • Overall response rate (complete response and partial response) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Graded according to standard international response criteria. Summarized by treatment arm in each cohort.

  • Rate of grade 3 or 4 non-hematologic toxicity thought to be possibly or likely related to study drugs, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Summarized by treatment arm in each cohort.

  • Percentage of patients treated and become appropriate candidates for allogeneic transplant [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Summarized by treatment arm in each cohort.


Estimated Enrollment: 196
Study Start Date: August 2006
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
Patients receive azacitidine subcutaneously once daily on days 1-10.
Drug: azacitidine
Given subcutaneously
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Experimental: Arm II
Patients receive azacitidine as in arm I and oral entinostat on days 3 and 10.
Drug: entinostat
Given orally
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: azacitidine
Given subcutaneously
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza

Detailed Description:

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

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 (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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00313586

  Show 232 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Steven Gore Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00313586     History of Changes
Other Study ID Numbers: NCI-2009-01077, NCI-2009-01077, ECOG-E1905, CDR0000466186, E1905, E1905, U10CA021115
Study First Received: April 11, 2006
Last Updated: October 25, 2013
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on April 17, 2014