A Phase II Trial of Fenretinide (4-HPR) in Biochemically Recurrent, Hormone Naive Prostate Cancer

Inclusion Criteria:

- Patient must have a histologically or cytologically confirmed history of
adenocarcinoma of the prostate

- Patients must have a rising PSA, following a nadir value of < 4 ng/mL for patients
treated with primary radiation and < 0.3 ng/mL for patients treated with radical
prostatectomy, with no clinical or radiographic evidence of metastatic disease; the
rising PSA must be confirmed by two consecutive increases, separated by at least 2
weeks; the absolute PSA value must be > 2.0 ng/mL, and the increment of increase must
be at least 0.5 ng/mL above the nadir

- Following radical prostatectomy, patients can have received adjuvant radiation
therapy for positive margins or pT3 disease; patients may also have received
radiation therapy for local recurrence, provided that they subsequently have a rising
PSA after a new PSA nadir of < 4ng/mL

- Bone scan negative for metastatic disease within 4 weeks prior to registration

- Patients must have a performance status of 0, 1, or 2

- The effects of fenretinide on fetal conception and development at the recommended
therapeutic dose are unknown; for this reason, men enrolled in this trial must agree
to use adequate contraception prior to study entry and for the duration of study
participation

- Peripheral absolute neutrophil count (ANC) >= 1000/μL

- Platelet count >= 100,000/μL (transfusion independent; defined as: without
transfusion for 3 weeks prior to obtaining study entry value)

- Hemoglobin >= 8.0 gm/dL (may receive RBC transfusions or exogenous erythropoietin)

- Life expectancy of greater than 3 months

- Serum creatinine =< 1.5 gm/dL

- Creatinine clearance or radioisotope GFR >= 50 ml/min/m2

- Total bilirubin =< 1.5 mg/dL

- SGOT (AST) and SGPT (ALT) < 2.5 x normal

- Patients with seizure disorders may be enrolled if on anticonvulsants and well
controlled

- CNS toxicity =< Grade 2

- Patient must be able to consume the entire intact capsule(s) in the dosage prescribed
for body surface area

- Triglycerides are less than 300mg/dl

- All patients will have malignancy confirmed by review of their biopsy specimens by
the Division of Pathology of the City of Hope National Medical Center, the University
of Southern California/LA County/Norris Comprehensive Cancer Center, or the
University of California at Davis

- In patients who received radiotherapy, the absolute increase of PSA must be at least
2ng/ml to account for the "bounce" phenomenon

Exclusion Criteria:

- Patients with evidence of metastatic disease

- PSA progression not verified by sequential rising PSA as discussed in Eligibility
section

- Inability to take oral fenretinide

- Patients who have had prior cytotoxic chemotherapy or androgen ablative therapy

- Patients with history of receiving, or current administration of, chemotherapeutic
agents, biological response modifiers, or corticosteroids; patients are permitted to
have received up to 9 months of neoadjuvant or adjuvant hormone ablation in
conjunction with their primary definitive therapy; androgen deprivation must have
been completed at least one year prior to registration; no complementary or
alternative therapy (e.g. St. John's Wort, PC-SPES, or other herbal remedies taken
for the purpose of treating prostate cancer) may be given during protocol treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to fenretinide (i.e. retinoids)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/ social situations that would limit compliance
with study requirements

- No prior malignancy is allowed except for the following: adequately treated basal
cell or squamous cell skin cancer, in situ carcinoma of any site, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease-free for 5 years

- Patients should not take any drugs suspected of causing pseudotumor cerebri, which
include tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides,
lithium, amiodarone, or vitamin A

- Patients may have received one prior investigational anti-cancer agent

- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
this study because of possible pharmacokinetic interactions with fenretinide;
appropriate studies will be undertaken in patients receiving combination
anti-retroviral therapy when indicated

- Patients should not concurrently take medications that may potentially act as
modulators of intracellular ceramide levels or ceramide cytotoxicity, sphingolipid
transport, or p-glycoprotein (MDR1) or MRP1 drug/lipid transporters, such as:
cyclosporine A or analogue; verapamil; tamoxifen or analogue; ketoconazole,
chlorpromazine; RU486; indomethacin; or sulfinpyrazone

- Patients with known uncontrolled hypertriglyceridemia resulting in pancreatitis are
excluded from study; patients with fasting triglycerides equal to or greater then
300mg/dl should start on medical treatment for hypertriglyceridemia (ex. fibrate
derivatives); fenretinide will only be started when triglycerides are less than
300mg/dl

- Patients with known retinopathy from any source are excluded from the protocol as
elevated ceramide levels from Fenretinide may exacerbate and/or lead to permanent
retinal damage in this population

- Patients taking antioxidant supplements (vitamin C or E) must discontinue use before
being eligible for protocol