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

Alternate Title

Phenylbutyrate and Tretinoin in Treating Patients With Hematologic Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	NCI	JHOC-J9879 JHOC-99072306, NCI-T98-0068, NCT00006239, T98-0068

Objectives

1. Determine the safety and toxicity of phenylbutyrate and tretinoin in patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.
2. Determine the pharmacokinetic interaction of this regimen in these patients.
3. Determine any potential therapeutic activity of this regimen in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed myelodysplastic syndrome (MDS)
  • Refractory anemia
  • Primary refractory leukopenia or thrombocytopenia with morphologic features of MDS
  • Refractory anemia with excess blasts (RAEB)
  • Refractory anemia with ringed sideroblasts
  • RAEB in transformation
  • Must have excess blasts or be hematopoietically compromised, defined as one of the following:
    • RBC transfusion dependent
    • Granulocyte count less than 1,000/mm³
    • Platelet count less than 50,000/mm³

  OR

• Diagnosis of chronic myelomonocytic leukemia
  • Hematopoietically compromised (as defined above)

    OR

  • Excess blasts

    OR

  • Evaluable disease related symptomatology (organomegaly or leukemia cutis)

  OR

• Diagnosis of acute myeloid leukemia
  • WBC less than 20,000/mm³ and stable for at least 2 weeks
  • Unlikely to require cytotoxic therapy during study
• No CNS or pulmonary leukostasis or CNS leukemia

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• At least 3 weeks since prior biologic therapy, including hematopoietic growth factors, and recovered

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks (1 month for MDS patients) since prior chemotherapy and recovered

Endocrine therapy:

• Not specified

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)
• No disseminated intravascular coagulation

Hepatic:

• Bilirubin less than 2.0 mg/dL (unless due to hemolysis or Gilbert's syndrome)

Renal:

• Creatinine less than 2.0 mg/dL

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 2 weeks prior, during, and for 3 months after study
• No active infection

Expected Enrollment

A total of 3-24 patients will be accrued for this study within 18 months.

Outline

This is a dose escalation study of tretinoin.

Patients receive phenylbutyrate IV continuously on days 1-7 of weeks 1, 5, 7, 9, 11, 13, 15, 17, and 19. Patients also receive oral tretinoin three times daily on days 1-7 of weeks 3, 5, 7, 9, 11, 13, 15, 17, and 19. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tretinoin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose limiting toxicities.

An additional cohort of 6 patients is accrued at the MTD. These patients receive phenylbutyrate IV continuously on days 1-3 of weeks 1 and 3-18. These patients also receive oral tretinoin three times daily on days 1-3 of weeks 2-18. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

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		A Phase I, Dose-Finding Trial of Sodium Phenylbutrate (NSC 657802) in Combination with All Trans-retinoic Acid (ATRA, NSC 122758) in Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
Trial Start Date		2000-12-20
Registered in ClinicalTrials.gov		NCT00006239
Date Submitted to PDQ		2000-07-24
Information Last Verified		2005-03-01
NCI Grant/Contract Number		P30-CA06973, R01-CA67803

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