Preneoplastic Conditions, Prostatic Intraepithelial Neoplasia
Conditions
Keywords
neoplasia, chemoprevention, cancer, premalignant, precancerous, Chemoprophylaxis, Intraepithelial Prostatic Neoplasia, Neoplasia, Prostatic Intraepithelial
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.
Interventions
DRUGToremifene 20 mg
The subject takes one dose by mouth of the 20mg Toremifine Citrate tablet once a day for the length of the trial (360 days).
DRUGPlacebo
The subject takes a placebo tablet identical in appearance to the toremifene 20mg tablet, administered by mouth daily for 360 days.
Sponsors
GTx
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
30 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Toremifene in the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN) | The outcome measurement time is up to 36 months | To measure the efficacy of toremifene citrate in men with high grade prostatic intraepithelial neoplasia (PIN). Prostate cancer-free survival distributions (Kaplan-Meier) |
| Occurrence of a Positive Cancer Biopsy | Up to 36 months | To measure the occurrence of a positive cancer biopsy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Toremifene on Total PSA (Prostate Specific Antigen) Levels | Up to 36 months | To assess the effect of toremifene in the total PSA (prostate specific antigen) levels from baseline |
| The Effect of Toremifene on the Mean Change at 36 Months in AUA (American Urological Association) Symptom Score | 36 months | 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 |
| The Effect of Toremifene on Lipid Levels | Up to 36 months | Measure lipid levels including total cholesterol, LDL, HDL and Triglycerides % change from baseline |
| The Effect of Toremifene on % Free Serum PSA (Prostate Specific Antigen) Levels, Change From Baseline | 36 months | To assess the effect of toremifene in % free serum PSA (prostate specific antigen) levels, change from baseline |
| Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | Up to 36 months | To measure the occurrence of high grade PIN at the 12, 24, 36 Month intervals in the 360 days study. |
| The Effect of Toremifene on Hormone Levels | Up to 36 months | % Change from baseline hormone levels, including total testosterone, free testosterone, dihydrotestosterone (DHT) and estradiol |
Countries
Argentina, Canada, United States
Participant flow
Recruitment details
1,589 subjects were recruited
Participants by arm
| Arm | Count |
|---|---|
| Toremifene 20mg toremifene 20mg arm | 787 |
| Placebo Placebo group | 802 |
| Total | 1,589 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 60 | 64 |
| Overall Study | Cardiologist recommendation | 1 | 0 |
| Overall Study | Failure to comply w/dosing regimen | 6 | 4 |
| Overall Study | Lost to Follow-up | 23 | 18 |
| Overall Study | mililtary deployment | 2 | 0 |
| Overall Study | Not able to discontinue plavix | 0 | 1 |
| Overall Study | Physician Decision | 18 | 21 |
| Overall Study | Protocol Violation | 13 | 18 |
| Overall Study | Pt. moved to another state | 1 | 0 |
| Overall Study | QTc>480 | 3 | 1 |
| Overall Study | Study Site Closing/PI Moved | 1 | 2 |
| Overall Study | Taking exclusionary avodart | 1 | 0 |
| Overall Study | Withdrawal by Subject | 75 | 70 |
Baseline characteristics
| Characteristic | Toremifene 20mg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 362 Participants | 368 Participants | 730 Participants |
| Age, Categorical Between 18 and 65 years | 425 Participants | 434 Participants | 859 Participants |
| Age, Continuous | 64.4 years STANDARD_DEVIATION 7.45 | 64.4 years STANDARD_DEVIATION 7.96 | 64.4 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment Argentina | 8 participants | 10 participants | 18 participants |
| Region of Enrollment Canada | 97 participants | 104 participants | 201 participants |
| Region of Enrollment United States | 682 participants | 688 participants | 1370 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 787 Participants | 802 Participants | 1589 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 666 / 802 | 631 / 787 |
| serious Total, serious adverse events | 137 / 802 | 117 / 787 |
Outcome results
Primary
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)
Time frame: The outcome measurement time is up to 36 months
Population: MITT: Randomized subjects who were given study drug and did not return it unused and had a baseline and on-study prostate biopsy
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Efficacy of Toremifene in the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN) | 54.9 % of participants cancer-free 36 months | 95% Confidence Interval 36 |
| Toremifene 20mg | Efficacy of Toremifene in the Prevention of Prostate Cancer in Men With High Grade Prostatic Intraepithelial Neoplasia (PIN) | 59.5 % of participants cancer-free 36 months | 95% Confidence Interval 36 |
Primary
Occurrence of a Positive Cancer Biopsy
To measure the occurrence of a positive cancer biopsy
Time frame: Up to 36 months
Population: Modified, intend-to-treat (MITT) all randomized subj. who take at least 1 dose of study drug, and had baseline and on-study prostate biopsies, where the baseline biopsy did not have cancer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Occurrence of a Positive Cancer Biopsy | 23.5 Months |
| Toremifene 20mg | Occurrence of a Positive Cancer Biopsy | 15.9 Months |
Secondary
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.
Time frame: Up to 36 months
Population: All randomized subjects that took 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 12 months | 167 Subjects |
| Placebo | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 24 months | 90 Subjects |
| Placebo | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 36 months | 92 Subjects |
| Toremifene 20mg | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 12 months | 149 Subjects |
| Toremifene 20mg | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 24 months | 103 Subjects |
| Toremifene 20mg | Occurrence of High Grade PIN at the 12, 24, 36 Month Biopsies | 36 months | 94 Subjects |
Secondary
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
Time frame: 36 months
Population: Any randomized subject taking at least 1 dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Effect of Toremifene on % Free Serum PSA (Prostate Specific Antigen) Levels, Change From Baseline | 2.3 mcg/L | Standard Deviation 11.24 |
| Toremifene 20mg | The Effect of Toremifene on % Free Serum PSA (Prostate Specific Antigen) Levels, Change From Baseline | 2.0 mcg/L | Standard Deviation 10.49 |
Secondary
The Effect of Toremifene on Hormone Levels
% Change from baseline hormone levels, including total testosterone, free testosterone, dihydrotestosterone (DHT) and estradiol
Time frame: Up to 36 months
Population: Any randomized subject taking at least 1 dose of study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Effect of Toremifene on Hormone Levels | DHT | 17.736 % of change | Standard Deviation 48.3284 |
| Placebo | The Effect of Toremifene on Hormone Levels | Estradiol | 11.9 % of change | Standard Deviation 67.86 |
| Placebo | The Effect of Toremifene on Hormone Levels | Testosterone total | 2.246 % of change | Standard Deviation 102.9086 |
| Placebo | The Effect of Toremifene on Hormone Levels | Testosterone free | 17.71 % of change | Standard Deviation 438.652 |
| Toremifene 20mg | The Effect of Toremifene on Hormone Levels | Testosterone free | 7.92 % of change | Standard Deviation 65.114 |
| Toremifene 20mg | The Effect of Toremifene on Hormone Levels | DHT | 46.409 % of change | Standard Deviation 60.2061 |
| Toremifene 20mg | The Effect of Toremifene on Hormone Levels | Testosterone total | 31.136 % of change | Standard Deviation 63.5961 |
| Toremifene 20mg | The Effect of Toremifene on Hormone Levels | Estradiol | 53.2 % of change | Standard Deviation 151.5 |
Secondary
The Effect of Toremifene on Lipid Levels
Measure lipid levels including total cholesterol, LDL, HDL and Triglycerides % change from baseline
Time frame: Up to 36 months
Population: All randomized subjects who take at least 1 dose of study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Effect of Toremifene on Lipid Levels | Cholesterol | -3.678 % of change | Standard Deviation 18.2317 |
| Placebo | The Effect of Toremifene on Lipid Levels | LDL | -7.447 % of change | Standard Deviation 64.8765 |
| Placebo | The Effect of Toremifene on Lipid Levels | HDL | 3.69 % of change | Standard Deviation 19.133 |
| Placebo | The Effect of Toremifene on Lipid Levels | Triglycerides | 16.298 % of change | Standard Deviation 58.003 |
| Toremifene 20mg | The Effect of Toremifene on Lipid Levels | Triglycerides | 0.319 % of change | Standard Deviation 47.9793 |
| Toremifene 20mg | The Effect of Toremifene on Lipid Levels | Cholesterol | -6.675 % of change | Standard Deviation 116.9705 |
| Toremifene 20mg | The Effect of Toremifene on Lipid Levels | HDL | 0.29 % of change | Standard Deviation 16.65 |
| Toremifene 20mg | The Effect of Toremifene on Lipid Levels | LDL | -7.824 % of change | Standard Deviation 28.8209 |
Secondary
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
Time frame: 36 months
Population: Reference to J Urol.1992 Nov;148(5):1549-57; discussion 1564. AUA symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Assocciation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Effect of Toremifene on the Mean Change at 36 Months in AUA (American Urological Association) Symptom Score | 1.1 scores on a scale | Standard Deviation 5.4 |
| Toremifene 20mg | The Effect of Toremifene on the Mean Change at 36 Months in AUA (American Urological Association) Symptom Score | 1.2 scores on a scale | Standard Deviation 5.6 |
Secondary
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
Time frame: Up to 36 months
Population: Any randomized subject taking at least 1 dose of study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Effect of Toremifene on Total PSA (Prostate Specific Antigen) Levels | 0.82 mcg/L | Standard Deviation 7.36 |
| Toremifene 20mg | The Effect of Toremifene on Total PSA (Prostate Specific Antigen) Levels | 1.07 mcg/L | Standard Deviation 3.632 |