Thalidomide for the Treatment of Hormone-Dependent Prostate Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Thalidomide; Drug: leuprolide acetate; Drug: goserelin; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Florida
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital, Fort Lauderdale
  • Louisiana
    • New Orleans, Louisiana, United States, 70112-2282
      • Louisiana State University
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health, Clinical Center, 9000 Rockville Pike
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University Hutzel Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • University of Minnesota
  • New York
    • New York, New York, United States, 10032-3784
      • Columbia University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
  • Virginia
    • Portsmouth, Virginia, United States, 23708
      • Naval Medical Center, Portsmouth
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Thalidomide; Study participants are randomly assigned to one of two treatment groups. Participants received leuprolide or goserelin for 6 months. In period 1 participants received thalidomide orally 200 mg a day. Patients will be followed until PSA progression defined as prostate-specific antigen (PSA) level that returns to what it was before beginning leuprolide or goserelin or to 5 nanograms per liter, whichever is lower. The participants are returned to the leuprolide or goserelin treatment for 6 months. In period 2 participants received the placebo for thalidomide once a day.	Drug: Thalidomide; Thalidomide 200 mg given orally every evening at 9pm. Treatment may continue indefinitely provided that there are no dose-limiting toxicity.; Other Names: Thalomid; Drug: leuprolide acetate; Injections of leuprolide once a month for six months.; Other Names: leuprorelin; Drug: goserelin; Injections of Goserelin once a month for six months.; Other Names: Zolodex
EXPERIMENTAL: Placebo; Study participants are randomly assigned to one of two treatment groups. Participants received leuprolide or goserelin for 6 months. In period 1 participants received placebo for thalidomide. Patients will be followed until PSA progression defined as prostate-specific antigen (PSA) level that returns to what it was before beginning leuprolide or goserelin or to 5 nanograms per liter, whichever is lower. The participants are returned to the leuprolide or goserelin treatment for 6 months. In period 2 participants received thalidomide 200 mg once a day.	Drug: leuprolide acetate; Injections of leuprolide once a month for six months.; Other Names: leuprorelin; Drug: goserelin; Injections of Goserelin once a month for six months.; Other Names: Zolodex; Other: Placebo; Patients will receive the placebo if they initially received thalidomide. The starting dose of placebo 200 mg (four capsules of 100-50 mg capsules) orally once daily at bedtime.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Progression	Time to progression is defined as follows: if the PSA returns to baseline (defined as the PSA value prior to starting leuprolide or goserelin) or increases to the absolute value of 5 ng/ml.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With Adverse Events	Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.	Date treatment consent signed to date off study, approximately 60 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Wayne State University; Columbia University; University of Pittsburgh; University of Washington; University of Minnesota; Louisiana State University Health Sciences Center in New Orleans; United States Naval Medical Center, Portsmouth; Holy Cross Hospital, Fort Lauderdale
• Investigators: Principal Investigator: William L Dahut, M.D., National Cancer Institute, National Institutes of Heath

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• MedlinePlus
• Drug Information Portal
• U.S. FDA Resources

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2000
• Primary Completion (ACTUAL): January 30, 2005
• Study Completion (ACTUAL): March 30, 2010

Study Registration Dates

• First Submitted: February 19, 2000
• First Submitted That Met QC Criteria: February 19, 2000
• First Posted (ESTIMATE): February 21, 2000

Study Record Updates

• Last Update Posted (ACTUAL): May 22, 2018
• Last Update Submitted That Met QC Criteria: April 13, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Thalidomide; Cancer; Prostate Cancer; Angiogenesis; Prostate; Hormonal Therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Thalidomide; Leuprolide; Goserelin
• Other Study ID Numbers: 000080 (OTHER: Clinical Center, NIH); 00-C-0080 (OTHER: Clinical Center, NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No