Thalidomide for the Treatment of Hormone-Dependent Prostate Cancer

This is a double-blind randomized phase III study designed to determine if thalidomide can
improve the efficacy of the luteinizing hormone releasing hormone (LHRH) agonist (leuprolide
or goserelin) in hormone-responsive patients with a rising PSA after primary definitive
therapy for prostate cancer. Patients with only a rising PSA will be randomized to LHRH
agonist for six months followed by oral thalidomide 200 mg per day or placebo (phase A). At
the time of PSA progression, an LHRH agonist will be restarted for six additional months.
After six months, patients originally treated with thalidomide will be crossed over to
placebo and patients originally treated with placebo will be crossed over to thalidomide and
followed until PSA progression or the development of metastatic disease, whichever occurs
first (Phase B). Additional information will be obtained on changes in the circulating levels
of the following growth factors: basic fibroblast growth factor (bFGF), tumor necrosis factor
(TNF), vascular endothelial growth factor (VEGF), and transforming growth factor beta
(TGFbeta). Likewise we will monitor changes in testosterone and dihydrotestosterone (DHT)
throughout the study. Neurological complications are the primary dose-limiting toxicity
anticipated with chronic thalidomide administration.

- Inclusion Criteria:

- patients must have prostate specific antigen (PSA) only androgen dependent
adenocarcinoma of the prostate. All patients must have failed definitive therapy
(radical prostatectomy, radiation therapy with external beam or brachytherapy,or
cryosurgery).

- Patients must have a negative Computerized Tomography (CT) scan and Bone Scan for
metastatic prostate cancer.

- Patients must have histopathological documentation of prostate cancer. Every attempt
should be made to have slides and blocks reviewed at National Cancer Institute (NCI)
Pathology laboratory. The review of pathology by the NCI will not delay enrollment.

- Patients must have progressive prostate cancer. Two consecutively rising PSAs above
the nadir post-definitive therapy and an absolute value greater than 1.0 ng/ml
separated by at least 2 weeks.

- Patients must have a life expectancy of more than 12 months.

- Patients must have a performance status of 0 to 2 according to the Eastern Cooperative
Oncology Group (ECOG) criteria.

- Hematological eligibility parameters (within 2 weeks of starting therapy):

Granulocyte count greater than or equal to 1,000/mm^3. Platelet count greater than or equal
to 75,000/mm^3.

- Biochemical eligibility parameters (within 2 weeks of starting therapy): If the
creatinine is greater than 2.0 mg/dL obtain a 24 hour urine collection.

Creatinine clearance must be greater than 40 mL/min. Hepatic function:

bilirubin (total) less than or equal to 1 mg/dL upper limit of normal; Alanine
aminotransferase (ALT) less than 2.5 times upper limit of normal.

- Exception: Patients with Clinical Gilbert's Syndrome may have total bilirubin less
than or equal to 2.5 mg/dL.

- Patients must not have other concurrent malignancies (within the past 2 years) with
the exception of nonmelanoma skin cancer and Rai Stage 0 chronic lymphoma leukemia),
in situ carcinoma of any site, or life threatening illnesses, including untreated
infection (must be at least 1 week off intravenous antibiotic therapy before beginning
thalidomide).

- Patients with a history of unstable or newly diagnosed angina pectoris, recent
myocardial infarction (within 6 months of enrollment), New York class II-IV congestive
heart failure, chronic obstructive lung disease requiring oxygen therapy, uncontrolled
seizure activity or by medical judgement of the physician, are not eligible.

- Patients must be able to understand and sign an informed consent document.

- Patients must be willing to travel from their home to the NIH or the participating
institution (Louisiana State Univ., Univ. of Washington, Columbia University,Wayne
State, University of Minnesota, University of Pittsburgh, Holy Cross)for follow-up
visits (due to sedation associated with thalidomide). It is preferred that patients
not drive the first 3 days of taking daily dosing,or if sedation appears to be a
continuing complication).

- Patients must be greater than or equal to 18 years of age.

- Male patients must be counseled about the possibility that thalidomide may be present
in semen. Men must use a latex condom every time they have sexual intercourse with
women during therapy and for 8 weeks after discontinuing thalidomide, even if they
have had a successful vasectomy.

- Patients may enroll as a late entry if the following criteria are met: Have received
leuprolide or goserelin within 3 months of starting study,have a PSA within two weeks
of hormonal injection and have a bone scan without metastasis within 8 weeks of
enrollment.

- Patients with Rai Stage of Chronic Lymphocytic Leukemia (lymphocytosis only) will be
eligible.

- Exclusion Criteria:

- Patients that have received leuprolide, diethylstilbestrol (DES), flutamide,
bicalutamide, PC stands for prostate cancer and SPES is the Latin word for
hope)PC-SPES, goserelin, cytotoxic chemotherapy, finasteride and/or nilutamide within
the past year (or currently) are not eligible. Patients that received these agents for
adjuvant or neoadjuvant therapy at the time of definitive therapy are eligible.
Exception: Patients enrolled under late entry criteria, who have received
leuprolide/goserelin within 3 months of starting study are eligible.

- Patients with National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP)
grade 2 or greater peripheral neuropathy of any cause that is clinically detectable,
patients receiving anti-convulsive medications, and patients with a history of
seizures within the past 10 years will not be eligible for this study.

- Patients who are receiving sedative/hypnotic agents (i.e. benzodiazepines) which
cannot be discontinued, will not be eligible for this study. Patients who have had a
surgical orchiectomy will not be eligible for this study.

- Patients who received a systemic chemotherapy for prostate cancer will not be
eligible.

- Patients with a confirmed psychiatric history of a major depression consistent with
American Psychiatric Association Diagnostic and Statistical Manual (DSM IIIR
criteria), confirmed by a psychiatrist will not be eligible.