Phenylbutyrate and Tretinoin in Treating Patients With Hematologic Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Drug: sodium phenylbutyrate
* Drug: tretinoin


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: sodium phenylbutyrate|nan|
|Drug: tretinoin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia, previously treated myelodysplastic syndromes, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)