Fenretinide in Treating Patients With Metastatic or Unresectable Malignant Solid Tumors

OBJECTIVES:

• Determine the maximum tolerated dose of fenretinide in patients with metastatic or unresectable malignant solid tumors.
• 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 dose-escalation, multicenter study.

Patients receive fenretinide IV continuously on days 1-5. Treatment repeats every 3 weeks 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 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 dose-limiting toxicity. At least 6 patients are treated at the MTD.

Patients undergo blood sample collection to determine plasma concentrations (pharmacokinetics) of fenretinide periodically during course 1 and at the end of courses 2-6.

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: A total of 21 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed solid tumor malignancy

• Metastatic and/or unresectable disease
• No standard curative or palliative measures exist or remain effective
• Measurable or evaluable disease
• No known brain metastases unless previously resected or irradiated with no treatment with steroids for more than 1 month

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
• Life expectancy > 3 months
• WBC ≥ 3,000/mm³
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 75,000/mm³
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (5 times ULN for patients with known liver metastases)
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for ≥ 6 months after completion of study treatment
• No uncontrolled diabetes mellitus at high risk for hypertriglyceridemia (i.e., fasting serum glucose concentration > 200 mg/dL OR hemoglobin A1C > 7.5%)
• No egg allergy
• No history of allergic reactions to compounds of similar chemical or biologic composition to fenretinide (e.g., isotretinoin, vitamin A, or tretinoin)
• No uncontrolled intercurrent illness including, but not limited to, any of the following:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situation that would preclude compliance with study requirements
• No known hypertriglyceridemia requiring medication
• No identified familial hyperlipidemia disorder

PRIOR CONCURRENT THERAPY:

• Recovered from all prior therapy
• Prior treatment with oral fenretinide is allowed provided no severe toxicity occurred
• At least 2 weeks since prior major surgery
• More than 4 weeks since prior chemotherapy or radiotherapy

• At least 6 weeks since prior nitrosoureas or mitomycin C
• No other concurrent investigational agents
• No other concurrent anticancer chemotherapy
• No other concurrent antioxidants*
• No concurrent hormone-ablative agents, including steroids, except for adrenal replacement or anti-inflammatory indications
• No other concurrent anticancer agents or therapies
• 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, p-glycoprotein, multidrug resistance protein 1 (MRP1), or MRP1 drug/lipid transporters, including any of the following*:

• Cyclosporine or any of its analogues
• Verapamil
• Tamoxifen or its analogue
• Ketoconazole
• Chlorpromazine
• Mifepristone
• Indomethacin
• Sulfinpyrazone NOTE: *Patients who have discontinued these drugs for ≥ 1 week are eligible
• No concurrent medications that may cause pseudotumor cerebri, including any of the following:

• Tetracycline
• Nalidixic acid
• Nitrofurantoin
• Phenytoin
• Sulfonamides
• Lithium
• Amiodarone
• No concurrent total parenteral nutrition (TPN) with intralipids
• No concurrent combination antiretroviral therapy for HIV-positive patients