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Azacitidine Plus Phenylbutyrate in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00004871
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : March 10, 2010
National Cancer Institute (NCI)
Information provided by:
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:

RATIONALE: Azacitidine plus phenylbutyrate may help leukemia cells develop into normal white blood cells.

PURPOSE: Phase I trial to study the effectiveness of combining azacitidine and phenylbutyrate in treating patients who have acute myeloid leukemia or myelodysplastic syndrome.

Condition or disease Intervention/treatment Phase
Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases Drug: azacitidine Drug: sodium phenylbutyrate Phase 1

Detailed Description:


  • Determine the safety and toxicity of azacitidine in combination with phenylbutyrate in patients with recurrent, refractory, or untreated acute myeloid leukemia or myelodysplastic syndrome.
  • Determine the minimal effective pharmacologic dose of azacitidine required to consistently inhibit DNA methyltransferase in this patient population.
  • Obtain preliminary clinical and/or laboratory data suggesting potential therapeutic activity of this combination regimen in these patients.

OUTLINE: This is a dose deescalation study of azacitidine.

Patients receive azacitidine subcutaneously daily on days 1-5 and 29-33 followed by phenylbutyrate IV continuously on days 5-12 and 33-40. Treatment continues for at least 2 courses in the absence of disease progression. Patients with responsive disease may receive an additional 2 months of therapy.

Cohorts of 3-6 patients receive deescalating doses of azacitidine until the minimal effective pharmacologic dose (MEPD) is determined. The MEPD is defined as the dose above the dose at which more than 1 of 6 patients do not meet the target enzyme inhibition of greater than 90%.

Once the MEPD and toxicity have been established for a 5 day schedule, daily dose schedule of azacitidine is increased to 10, 14, and 21 days, followed by phenylbutyrate for 7 days. Courses are repeated every 28 days.

PROJECTED ACCRUAL: Approximately 32 patients will be accrued for this study within 2 years.

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Study Type : Interventional  (Clinical Trial)
Primary Purpose: Treatment
Official Title: Phase I, Dose De-Escalation to Minimal Effective Pharmacologic Dose Trial of Sodium Phenylbutyrate (PB, NSC 657802) in Combination With 5-Azacytidine (5-AZA, NSC 102816) in Patients With Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
Study Start Date : May 2000

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically or cytologically confirmed myelodysplastic syndrome (MDS) indicating one of the following:

    • Refractory anemia (RA)
    • Primary refractory leukopenia or thrombocytopenia with MDS morphology
    • RA with excess blasts (RAEB)
    • RA with ringed sideroblasts (RARS)
    • Chronic myelomonocytic leukemia
    • RAEB in transformation
  • RA or RARS must have at least one of the following:

    • Absolute neutrophil count less than 1,000/mm^3
    • Untransfused hemoglobin less than 8 g/dL
    • Platelet count less than 20,000/mm^3
    • Anemia
    • Thrombocytopenia requiring transfusion
    • High risk chromosomal abnormalities
  • Any stage of MDS allowed including:

    • Previously untreated MDS
    • Refractory MDS allowed if failure to achieve remission following prior intensive chemotherapy of at least 1 month ago
  • Relapsed, refractory, or untreated acute myeloid leukemia (AML) with the following:

    • WBC less than 30,000/mm^3
    • Stable for at least 2 weeks
    • Unlikely to require cytotoxic therapy during study
  • Untreated AML with poor risk factors for response to standard therapy including:

    • Greater than 60 years old
    • AML occurs in setting of antecedent hematologic disorder
    • High risk chromosomes (e.g., abnormalities of chromosome 5 or 7 or complex cytogenetic abnormalities)
    • Medical conditions that preclude cytotoxic chemotherapy as primary therapy
  • Refusal of cytotoxic chemotherapy allowed
  • No clinical evidence of CNS leukostasis or CNS leukemia



  • 18 and over

Performance status:

  • Zubrod 0-2

Life expectancy:

  • Not specified


  • See Disease Characteristics
  • Hemoglobin at least 8 g/dL (transfusion allowed)


  • Bilirubin less than 2.0 mg/dL (unless due to hemolysis or Gilbert's disease)


  • Creatinine less than 2.0 mg/dL


  • No disseminated intravascular coagulation


  • No pulmonary leukostasis


  • No active infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception 2 weeks prior, during and 3 months after study


Biologic therapy:

  • At least 3 weeks since prior biologic therapy including colony stimulating factors and recovered


  • See Disease Characteristics
  • At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy:

  • At least 3 weeks since prior hormonal therapy and recovered


  • At least 3 weeks since prior radiotherapy and recovered


  • Not specified

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00004871

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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
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Study Chair: Steven D. Gore, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Layout table for additonal information Identifier: NCT00004871    
Other Study ID Numbers: CDR0000067531, J9950
U01CA070095 ( U.S. NIH Grant/Contract )
R01CA067803 ( U.S. NIH Grant/Contract )
P30CA006973 ( U.S. NIH Grant/Contract )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: March 10, 2010
Last Verified: March 2010
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
recurrent adult acute myeloid leukemia
untreated adult acute myeloid leukemia
refractory anemia
refractory anemia with ringed sideroblasts
refractory anemia with excess blasts
refractory anemia with excess blasts in transformation
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
atypical chronic myeloid leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
4-phenylbutyric acid
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors