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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.
 
ClinicalTrials.gov Identifier: NCT00004871
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : March 10, 2010
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by:
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE March 7, 2000
First Posted Date  ICMJE January 27, 2003
Last Update Posted Date March 10, 2010
Study Start Date  ICMJE May 2000
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE Not Provided
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Azacitidine Plus Phenylbutyrate in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
Official Title  ICMJE 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)
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.

Detailed Description

OBJECTIVES:

  • 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
Intervention  ICMJE
  • Drug: azacitidine
  • Drug: sodium phenylbutyrate
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Enrollment  ICMJE Not Provided
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

Age:

  • 18 and over

Performance status:

  • Zubrod 0-2

Life expectancy:

  • Not specified

Hematopoietic:

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

Hepatic:

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

Renal:

  • Creatinine less than 2.0 mg/dL

Cardiovascular:

  • No disseminated intravascular coagulation

Pulmonary:

  • No pulmonary leukostasis

Other:

  • 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

PRIOR CONCURRENT THERAPY:

Biologic therapy:

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

Chemotherapy:

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

Endocrine therapy:

  • At least 3 weeks since prior hormonal therapy and recovered

Radiotherapy:

  • At least 3 weeks since prior radiotherapy and recovered

Surgery:

  • Not specified
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00004871
Other Study ID Numbers  ICMJE CDR0000067531, J9950
U01CA070095 ( U.S. NIH Grant/Contract )
R01CA067803 ( U.S. NIH Grant/Contract )
P30CA006973 ( U.S. NIH Grant/Contract )
JHOC-99072307
NCI-T99-0092
JHOC-J9950
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Steven D. Gore, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date March 2010

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