Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI JHOC-99072307 NCI-T99-0092, NCT00004871, T99-0092, JHOC-J9950

Objectives

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

Entry 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/mm³
  • Untransfused hemoglobin less than 8 g/dL
  • Platelet count less than 20,000/mm³
  • 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/mm³
  • 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

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

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

Expected Enrollment

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

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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Steven Gore, MD, Protocol chair		Ph: 410-955-8781 Email: gorest@jhmi.edu

Registry Information
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)
Trial Start Date		2000-05-18
Registered in ClinicalTrials.gov		NCT00004871
Date Submitted to PDQ		2000-01-05
Information Last Verified		2003-10-17
NCI Grant/Contract Number		CA06973, CA67803, CA70095