Thalidomide for the Treatment of Hormone-Dependent Prostate Cancer
Thalidomide for the Treatment of Hormone-Dependent Prostate Cancer
This multi-center study will evaluate whether thalidomide can improve the effectiveness of
 the drugs leuprolide or goserelin in treating testosterone-dependent prostate cancer.
 Leuprolide and goserelin-both approved to treat prostate cancer-reduce testosterone
 production, which, in most patients, reduces the size of the tumor. Thalidomide, a drug used
 for many years to treat leprosy, blocks the growth of blood vessels that may be important to
 disease progression.

 Patients 18 years or older with testosterone-dependent prostate cancer that has persisted or
 recurred after having had surgery, radiation therapy, or cryosurgery, but whose disease has
 not metastasized (spread beyond the prostate) may be eligible for this study. Candidates are
 screened with a medical history and physical examination, including blood tests, bone and
 computed tomography (CT) scans or other imaging studies.

 Study participants are randomly assigned to one of two treatment groups. One group receives
 leuprolide or goserelin followed by thalidomide; the other receives leuprolide or goserelin
 followed by placebo (a look-alike pill with no active ingredients). Patients in both groups
 receive an injection of leuprolide or goserelin once a month for 6 months. After that time
 they take four capsules of either thalidomide or placebo once a day and remain on the drug
 until their prostate-specific antigen (PSA) level returns to what it was before beginning
 leuprolide or goserelin or to 5 nanograms per liter, whichever is lower.(PSA is a protein
 secreted by the prostate gland. Monitoring changes in levels of this protein can help
 evaluate tumor progression). At this point the entire procedure begins again, starting with
 leuprolide or goserelin treatment, but the experimental drug is switched; patients originally
 treated with thalidomide are crossed over to placebo, and patients originally treated with
 placebo are crossed over to thalidomide.

 Patients are monitored periodically with the following tests and procedures:

 Medical histories and physical examinations. Blood and urine tests to monitor thalidomide and
 PSA levels, the response to treatment, and routine laboratory values (e.g., cell counts and
 kidney and liver function).

 Computed tomography (CT) and bone scans, and possibly other imaging tests to assess the
 tumor.

 Electromyography (EMG) and nerve conduction studies, as needed. For electromyography, a thin
 needle is inserted into a few muscles and the patient is asked to relax or to contract the
 muscles.
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.