Fenretinide in Treating Patients With Metastatic or Unresectable Malignant Solid Tumors

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 tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This phase I trial is studying the side effects and best dose of fenretinide in treating patients with metastatic or unresectable malignant solid tumors.

Detailed Description
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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.

Official Title
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Phase I Trial of Intravenous Fenretinide (4-HPR) for Patients With Malignant Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: fenretinide
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: fenretinide|4-HPR (Fenretinide) is given as a continuous intravenous infusion (CIV) for five consecutive days. Cycle is repeated every 3 weeks, if PR, CR or stable disease for 6 cycles.|
|Other: pharmacological study|samples drawn per protocol|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of fenretinide |  | at end of study | 
| Toxicity as measured by type (organ affected or laboratory determination such as absolute neutrophil count), severity (NCI CTCAE v3.0), time of onset (course number), duration, and reversibility or outcome |  | ongoing | 
| Survival and time to failure as measured by Kaplan-Meier |  | at end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific