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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Drug: azacitidine
* Drug: sodium phenylbutyrate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: azacitidine|nan|
|Drug: sodium phenylbutyrate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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