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)

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia; Myelodysplastic/Myeloproliferative Diseases
• Intervention / Treatment: Drug: azacitidine; Drug: sodium phenylbutyrate

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: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Steven D. Gore, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: May 1, 2000
• Primary Completion: December 7, 2022
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: March 7, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): March 10, 2010
• Last Update Submitted That Met QC Criteria: March 9, 2010
• Last Verified: March 1, 2010

More Information

Terms related to this study

• Keywords: 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; recurrent adult acute myeloid leukemia; untreated adult acute myeloid leukemia; atypical chronic myeloid leukemia; myelodysplastic/myeloproliferative disease, unclassifiable
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; 4-phenylbutyric acid
• Other Study ID Numbers: CDR0000067531, J9950; P30CA006973 (U.S. NIH Grant/Contract); U01CA070095 (U.S. NIH Grant/Contract); R01CA067803 (U.S. NIH Grant/Contract); JHOC-99072307; NCI-T99-0092; JHOC-J9950

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No