Phenylbutyrate and Tretinoin in Treating Patients With Hematologic Cancer

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT00006239

Collaborator

National Cancer Institute (NCI) (NIH)

Location

Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Tretinoin may help hematologic cancer cells develop into normal white blood cells.

PURPOSE: Phase I trial to study the effectiveness of combining phenylbutyrate and tretinoin in treating patients who have hematologic cancer.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases	Drug: sodium phenylbutyrate Drug: tretinoin	Phase 1

Detailed Description

OBJECTIVES:

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

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.

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

Study Design

Study Type:

Interventional

Primary Purpose:

Treatment

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)

Study Start Date :

Dec 1, 2000

Actual Primary Completion Date :

Feb 1, 2005

Actual Study Completion Date :

Mar 1, 2005

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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/mm^3
Platelet count less than 50,000/mm^3 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/mm^3 and stable for at least 2 weeks
Unlikely to require cytotoxic therapy during study
No CNS or pulmonary 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)
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