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

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)


Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborator: National Cancer Institute (NCI)

Source 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.

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.

Overall Status Completed
Start Date May 2000
Phase Phase 1
Study Type Interventional

Intervention Type: Drug

Intervention Name: azacitidine

Intervention Type: Drug

Intervention Name: sodium phenylbutyrate




- 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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Steven D. Gore, MD Study Chair Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Location Countries

United States

Verification Date

March 2010

Has Expanded Access No
Condition Browse
Study Design Info

Primary Purpose: Treatment