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

NCT ID: NCT00004871

Last Updated: 2010-03-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-05-31

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.

Conditions

Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

Study Design

• Primary Study Purpose: TREATMENT

Interventions

azacitidine

Intervention Type: DRUG

sodium phenylbutyrate

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Principal Investigators

Steven D. Gore, MD

Role: STUDY_CHAIR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

U01CA070095

Identifier Type: NIH

Identifier Source: secondary_id

View Link

R01CA067803

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

JHOC-99072307

Identifier Type: -

Identifier Source: secondary_id

NCI-T99-0092

Identifier Type: -

Identifier Source: secondary_id

JHOC-J9950

Identifier Type: -

Identifier Source: secondary_id

CDR0000067531, J9950

Identifier Type: -

Identifier Source: org_study_id