Fenretinide in Treating Patients With Refractory or Relapsed Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fenretinide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving fenretinide in a different way may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of intravenous fenretinide in treating patients with refractory or relapsed hematologic cancer.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of intravenous emulsified fenretinide in patients with refractory or relapsed hematologic malignancies. Determine the toxic effects of this drug in these patients. Determine the pharmacokinetics and in vivo activity of this drug in these patients. Determine, preliminarily, disease or tumor response in patients treated with this drug. OUTLINE: This is a pilot, dose-escalation, multicenter study. Patients receive emulsified fenretinide IV continuously over 5 days. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete or partial response may continue to receive fenretinide at the discretion of the study chair. Cohorts of 1 patient receive accelerated escalating doses of fenretinide until 2 patients experience moderate toxicity (cumulative across all dose levels) OR 1 patient experiences dose-limiting toxicity (DLT). After completion of the accelerated dose-escalation portion, the standard dose-escalation portion begins. Cohorts of 3-6 patients receive escalating doses of fenretinide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience DLT. At least 6 patients are treated at the MTD. An additional 12 patients are treated at the MTD. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study.

Official Title
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Phase I Trial of Intravenous Fenretinide (4-HPR) for Patients With Hematologic Malignancies

Conditions
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Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: fenretinide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies: Non-Hodgkin's lymphoma (NHL) Hodgkin's lymphoma Multiple myeloma Acute lymphoblastic leukemia Acute myeloid leukemia Chronic hematologic malignancy with a poor prognosis (e.g., failed 3 prior standard therapies), including any of the following: Chronic lymphocytic leukemia Chronic myelogenous leukemia Indolent NHL Myeloproliferative disorders Refractory or relapsed disease, as defined by 1 of the following: Resistant to standard therapy for refractory or relapsed disease Progressed after standard therapy for advanced disease No effective treatment exists Measurable or evaluable disease No active CNS disease Previously treated leptomeningeal disease or brain metastases allowed provided there is no evidence of remaining cancer by positron-emission tomography, MRI, or spinal fluid cytology PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 Life expectancy At least 3 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 (unless due to bone marrow involvement of disease) Platelet count ≥ 75,000/mm^3 (unless due to bone marrow involvement of disease) Hemoglobin ≥ 8.0 g/dL (transfusion allowed) No coagulation disorders Hepatic AST and ALT < 2.5 times upper limit of normal (ULN) (≤ 5 times ULN for patients with liver metastasis) Bilirubin ≤ 1.5 times ULN Renal Creatinine ≤ 1.5 times ULN Cardiovascular No major cardiovascular disease Pulmonary No major respiratory disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception prior to study entry, during study, and for at least 6 months after study participation No uncontrolled systemic infection No uncontrolled hypertriglyceridemia (i.e., triglyceride level > 500 mg/dL) No known HIV positivity No known allergy to egg products No known familial hyperlipidemia disorders No previously undiscovered hypertriglyceridemia No poorly controlled diabetes PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy More than 2 weeks since prior chemotherapy except hydroxyurea No concurrent hydroxyurea during study drug administration No other concurrent anticancer chemotherapy Endocrine therapy No concurrent hormone-ablative agents No concurrent steroids No concurrent tamoxifen or any of its analogues Radiotherapy No prior cranial radiotherapy More than 2 weeks since prior radiotherapy Surgery More than 20 days since prior surgery except for biopsy Other Recovered from all prior therapy More than 2 weeks since prior investigational agents No other concurrent investigational agents No other concurrent antineoplastic therapy No other concurrent antioxidants No concurrent herbal or other alternative therapies No concurrent vitamin supplements (e.g., vitamin A, ascorbic acid, or vitamin E) Standard dose multivitamin allowed No other concurrent medications that may act as modulators of intracellular ceramide levels or ceramide cytotoxicity, sphingolipid transport, or p-glycoprotein or multidrug resistance protein 1 (MRP1) drug/lipid transporters, including any of the following: Cyclosporine or any of its analogues Verapamil Ketoconazole Chlorpromazine Mifepristone Indomethacin Sulfinpyrazone No concurrent medications that may cause pseudotumor cerebri, including any of the following: Tetracycline Nalidixic acid Nitrofurantoin Phenytoin Sulfonamides Lithium Amiodarone No concurrent medication to control hypertriglyceridemia

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: fenretinide|Current dose level as an IV continuous infusion via central line over 5 days. Cycle is repeated every 3 weeks for up to 6 cycles|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose of fenretinide |  | participants will be followed for the duration of cycle 1, which is expected to be 3 weeks. | 
| To describe the toxicities of fenretinide |  | participants will be followed for the duration of treatment, which is expected to be 18 weeks or less | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent small lymphocytic lymphoma, recurrent mantle cell lymphoma, Waldenstrom macroglobulinemia, adult grade III lymphomatoid granulomatosis, recurrent adult grade III lymphomatoid granulomatosis, secondary acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult immunoblastic large cell lymphoma, refractory chronic lymphocytic leukemia, recurrent adult lymphoblastic lymphoma, recurrent adult Hodgkin lymphoma, refractory multiple myeloma, recurrent adult acute lymphoblastic leukemia, relapsing chronic myelogenous leukemia, chronic eosinophilic leukemia, primary myelofibrosis, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, stage II multiple myeloma, stage III multiple myeloma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, recurrent marginal zone lymphoma, splenic marginal zone lymphoma, recurrent adult acute myeloid leukemia