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

Inclusion Criteria

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