Fenretinide in Treating Patients With Refractory or Relapsed Hematologic Cancer

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.

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