Clinical trial NCT00004635: Thalidomide for the Treatment of Hormone-Dependent Prostate Cancer
Official title: A Double Blinded Randomized Crossover Phase III Study of Oral Thalidomide Versus Placebo in Patients With Stage D0 Androgen Dependent Prostate Cancer Following Limited Hormonal Ablation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: Angiogenesis
Cancer
Hormonal Therapy
Prostate
Thalidomide
Prostate Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Holy Cross Hospital, Fort Lauderdale
name: Louisiana State University Health Sciences Center in New Orleans
name: Wayne State University
name: University of Minnesota
name: Columbia University
name: University of Pittsburgh
name: United States Naval Medical Center, Portsmouth
name: University of Washington
First posted: 2000-02-21
Enrollment: 159
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Time to Progression
timeFrame: 36 months
Secondary outcomes:
measure: The Number of Participants With Adverse Events
timeFrame: Date treatment consent signed to date off study, approximately 60 months
Other outcomes:
Locations:
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital, Fort Lauderdale
state: Florida
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Bethesda
country: United States
facility: National Institutes of Health, Clinical Center, 9000 Rockville Pike
state: Maryland
city: Detroit
country: United States
facility: Wayne State University Hutzel Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Portsmouth
country: United States
facility: Naval Medical Center, Portsmouth
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: National Cancer Institute, National Institutes of Heath
name: William L Dahut, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aronson IK, Yu R, West DP, Van den Broek H, Antel J. Thalidomide-induced peripheral neuropathy. Effect of serum factor on nerve cultures. Arch Dermatol. 1984 Nov;120(11):1466-70. doi: 10.1001/archderm.120.11.1466.
citation: Bakay B, Nyhan WL. Binding of thalidomide by macromolecules in the fetal and maternal rat. J Pharmacol Exp Ther. 1968 Jun;161(2):348-60. No abstract available.
citation: Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide requires metabolic activation, which is species-dependent. Biochem Pharmacol. 1998 Jun 1;55(11):1827-34. doi: 10.1016/s0006-2952(98)00046-x.
citation: Figg WD, Hussain MH, Gulley JL, Arlen PM, Aragon-Ching JB, Petrylak DP, Higano CS, Steinberg SM, Chatta GS, Parnes H, Wright JJ, Sartor O, Dahut WL. A double-blind randomized crossover study of oral thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation. J Urol. 2009 Mar;181(3):1104-13; discussion 1113. doi: 10.1016/j.juro.2008.11.026. Epub 2009 Jan 23.
citation: Hawley JE, Pan S, Figg WD, Lopez-Bujanda ZA, Strope JD, Aggen DH, Dallos MC, Lim EA, Stein MN, Hu J, Drake CG. Association between immunosuppressive cytokines and PSA progression in biochemically recurrent prostate cancer treated with intermittent hormonal therapy. Prostate. 2020 Mar;80(4):336-344. doi: 10.1002/pros.23948. Epub 2020 Jan 3.