Prostate Cancer Prevention Study for Men With High Grade PIN (Prostatic Intraepithelial Neoplasia)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if toremifene citrate is effective and safe in the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia (PIN).

Detailed Description
-----------------
The purpose of this study is to determine if toremifene citrate is effective and safe in the prevention of prostate cancer in men who have been diagnosed with high grade prostatic intraepithelial neoplasia. Men who have ever been diagnosed with high grade PIN will be enrolled into an 36 month trial and will be assigned to either 20 mg of study drug or placebo per day. Subjects will undergo safety evaluations at Month 3, Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 along with prostate biopsies at Month 12 and Month 24 and Month 36 to determine efficacy.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Efficacy and Safety Study of Toremifene Citrate for the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN)

Conditions
-----------------
Preneoplastic Conditions, Prostatic Intraepithelial Neoplasia

Intervention / Treatment
-----------------
* Drug: Toremifene 20 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Give voluntary signed informed consent in accordance with institutional policies Be male, aged ≥ 30 years Have a diagnosis of high grade PIN from any previous prostate biopsy. The diagnosis of high grade PIN must be confirmed by the central pathologist Have had a prostate biopsy in the last 6 months with a minimum of 10 cores that shows no evidence of cancer as confirmed by the central pathologist; OR, have had 2 prostate biopsies (each with a minimum of 6 cores) in the 12 months prior to screening with at least one of the biopsies occurring within 6 months prior to the screening visit. Both biopsies should have no evidence of cancer as confirmed by the central pathologist Have a serum PSA of ≤ 10 ng/mL Agree to provide tablet containers for tablet counts and to complete a daily diary of study drug intake Agree to use an effective method of contraception, if the partner is of child-bearing age, while on study and for 30 days after the last dose of study medication Have adequate bone marrow, liver and renal function: White Blood Cell (WBC) Count ≥ 3,000/mm3; Platelet Count ≥ 100,000/mm3; Bilirubin ≤ 1.5 mg/dL; AST and ALT < 2x upper limit of normal; Serum Creatinine ≤ 2.0 mg% Exclusion Criteria: Previous exposure to toremifene citrate Have evidence of prostate cancer (local, regional and/or distal metastasis) Have any history of other malignancies (Exceptions include non-melanoma skin cancer or other cancer that has no evidence of tumor reoccurrence 5 years after definitive treatment). Have active systemic viral, bacterial, or fungal infections requiring treatment Have, in the judgment of the investigator, a clinically significant concurrent illness or psychological, familial, sociological, geographical or other concomitant condition that would not permit adequate follow-up and compliance with the study protocol Concurrently being treated with other investigational agents or have participated in an investigational study within 60 days prior to screening Currently taking dutasteride. Subject is eligible if he stops dutasteride for a total washout of 90 days prior to the Screening Visit and agrees not to use dutasteride for the duration of the study. Have previously taken finasteride for greater than two years Currently taking finasteride. Subject is eligible if he stops finasteride for a total washout of 30 days prior to the Screening Visit and agrees not to use finasteride for the duration of the study. Currently taking testosterone or testosterone-like supplements, such as dehydroepiandrosterone (DHEA). Subject is eligible if he stops these agents for a total washout of 30 days prior to the Screening Visit and agrees not to use these agents for the duration of the study. Have a history of taking PC-SPES within the past two years. Currently taking herbal medicine or dietary supplements for prostate health, such as Saw Palmetto (also known as Serenoa Repens). Subject is eligible if he stops these agents for a total washout of 30 days prior to taking the first dose of study drug and agrees not to use these agents for the duration of the study. Lycopene, vitamin E and selenium are not prohibited and no washout is required. However, vitamin E intake should be limited to less than 400 i.u. per day. Have a history of thromboembolic event or disease including deep vein thrombosis, pulmonary embolus, or thrombotic stroke History of chronic hepatitis or cirrhosis

Ages Eligible for Study
-----------------
Minimum Age: 30 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20 mg Toremifene Citrate<br>The subject takes one dose by mouth of the 20mg Toremifine Citrate tablet once a day for the length of the trial (360 days). | Drug: Toremifene 20 mg<br>* The subject takes one dose by mouth of the 20mg Toremifine Citrate tablet once a day for the length of the trial (360 days).<br>|
| Experimental: Placebo<br>The subject takes a placebo tablet identical in appearance to the toremifene 20mg tablet, administered by mouth daily for 360 days | Drug: Placebo<br>* The subject takes a placebo tablet identical in appearance to the toremifene 20mg tablet, administered by mouth daily for 360 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Toremifene in the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN) | To measure the efficacy of toremifene citrate in men with high grade prostatic intraepithelial neoplasia (PIN). Prostate cancer-free survival distributions (Kaplan-Meier) | The outcome measurement time is up to 36 months | 
| Occurrence of a Positive Cancer Biopsy | To measure the occurrence of a positive cancer biopsy | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Toremifene on Lipid Levels | Measure lipid levels including total cholesterol, LDL, HDL and Triglycerides % change from baseline | Up to 36 months | 
| The Effect of Toremifene on Hormone Levels | % Change from baseline hormone levels, including total testosterone, free testosterone, dihydrotestosterone (DHT) and estradiol | Up to 36 months | 
| The Effect of Toremifene on Total PSA (Prostate Specific Antigen) Levels | To assess the effect of toremifene in the total PSA (prostate specific antigen) levels from baseline | Up to 36 months | 
| The Effect of Toremifene on the Mean Change at 36 Months in AUA (American Urological Association) Symptom Score | To assess the effect of toremifene on the AUA (American Urological Association) symptom score mean change from baseline. Scores of 0-7=mild severity, 8-9, moderate, and 20-30, severe with possible responses of 0 (not at all) 1 (<1/5), 2 (<50% time), 3 (about 50% time), 4 (> 50% time) & 5 (Almost Always). There are 7 questions (1)Incomplete emptying (2)Frequency (3)Intermittency (4)Urgency (5)Weak-stream (6)Straining & (7)Nocturia. Analysis is change from baseline at final evaluation (36 months) for quality of life due to urinary symptoms. The P Value is from a Wilcoxon signed-rank test. Scores can range from 0-35, highest representing worse symptoms | 36 months | 
| Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | To measure the occurrence of high grade PIN at the 12, 24, 36 Month intervals in the 360 days study. | Up to 36 months | 
| The Effect of Toremifene on % Free Serum PSA (Prostate Specific Antigen) Levels, Change From Baseline | To assess the effect of toremifene in % free serum PSA (prostate specific antigen) levels, change from baseline | 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neoplasia, chemoprevention, cancer, premalignant, precancerous, Chemoprophylaxis, Intraepithelial Prostatic Neoplasia, Neoplasia, Prostatic Intraepithelial