A Selective Androgen Receptor Modulator for Symptom Management in Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This research study is studying the use of a targeted therapy called LY SARM, which is an investigational drug from a new class of molecules called Selective Androgen Receptor Modulators (SARMs) as a possible improvement in quality of life for participants who have undergone radical prostatectomy. Androgens are a group of hormones that play a role in male traits and reproductive activity. The names of the study interventions involved in this study are: - LY2452473

Detailed Description
-----------------
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved LY SARM/LY2452473 as a treatment for any disease. In this research study, the investigators are studying a new investigational drug called LY SARM (LY2452473). Concerns about the potential adverse effects of testosterone on the prostate have led to the development of molecules called SARMs (Selective Androgen Receptor Modulators). This investigational drug may improve sexual function, quality of life, muscle and bone mass in men with prostate cancer. This molecule was chosen because there is some evidence that shows it may help to improve sexual function and aid in the improvement of muscle mass while not having any influence on the prostate.

Official Title
-----------------
A Selective Androgen Receptor Modulator for Symptom Management in Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: LY2452473
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Age 19 years of age or older History of prostate cancer Stage pathological tumor-2 (pT2) N0, M0 lesions (If American Joint Committee on Cancer (AJCC) staging is not available in medical records, the investigators will infer the staging based on extensive review of the pathology report) Combined Gleason score < 7 (3+4) Radical prostatectomy two or more years ago Preoperative prostate-specific antigen (PSA)<10 ng/ml (if pre-operative PSA is not available in medical records, low-risk subjects with a Gleason score of 6(3+3) and who are at least 5 years out of surgery will be considered for enrollment) PSA <0.1 ng/mL using an assay that has a functional sensitivity of 0.1 ng/mL for at least two years after radical prostatectomy Serum testosterone, measured by Liquid chromatography-tandem mass spectrometry (LC-MS/MS), <300 mg/dL and/or free testosterone by equilibrium dialysis <60 pg/mL. * Derogatis Index of Sexual Function Male II (DISF-M-II) score ≤20, fatigue (FACIT-F score <30), or physical dysfunction (self-reported difficulty in walking a 1/4 mile or climbing two flights of stairs, short physical performance battery score 4 to 9). Ability to understand and the willingness to sign a written informed consent document. Agree to use adequate contraception prior to receiving the study drug, for the duration of study participation, and 4 months after completion of LY SARM administration. Exclusion Criteria History of radiation monotherapy History of androgen deprivation therapy Use of testosterone, dehydroepiandrosterone (DHEA), estrogens, gonadotropin-releasing hormone (GnRH) analogs, antiandrogens, spironolactone, ketoconazole, recombinant human growth hormone (rhGH), or megestrol acetate within the past 6 months Use of prednisone 20 mg daily or equivalent doses of other glucocorticoids for more than two weeks within the past 6 months Use of Clarithromycin, telithromycin, chloramphenicol, itraconazole, nefazodone, cobicistat within the past 6 months Use of penile implants, vacuum pump devices, intra-cavernosal injections Hematocrit >50% Serum creatinine >2.5 mg/dL Aspartate aminotransferase (AST) greater than 3x upper limit of normal (ULN) Alanine aminotransferase (ALT) greater than 3x ULN Hemoglobin A1c >7.5% Body mass index (BMI) >40 kg/m2 Diabetes requiring insulin therapy Severe untreated sleep apnea (treatment is defined as therapy with continuous positive airway pressure (CPAP), BiPAP, adaptive servo-ventilation (ASV), or other positive air pressure device) Uncontrolled heart failure (NYHA class 3 or 4) History of HIV Myocardial infarction within the last 3 months Acute coronary syndrome within the last 3 months Revascularization surgery within the last 3 months Stroke within the last 3 months Diagnosed schizophrenia or bipolar disorder or untreated depression Not appropriate for study based on physician discretion

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

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

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

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

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects who meet the eligibility criteria, will be randomized, to either placebo, LY SARM Dose 1, LY SARM Dose 2 or LY SARM Dose 3 daily, oral per cycle. | Drug: Placebo<br>* The participants will receive pills containing no active drug.<br>* Other names: Inactive comparator;|
| Active Comparator: LY2452473 Dose 1<br>Subjects who meet the eligibility criteria, will be randomized, to either placebo, LY SARM Dose 1, LY SARM Dose 2 or LY SARM Dose 3 daily, oral per cycle. | Drug: LY2452473<br>* LY2452473 is a selective androgen receptor modulator which is agonist on the muscle but which spares the prostate.<br>* Other names: Selective Androgen Receptor Modulator;|
| Active Comparator: LY2452473 Dose 2<br>Subjects who meet the eligibility criteria, will be randomized, to either placebo, LY SARM Dose 1 or LY SARM Dose 2 or LY SARM Dose 3 daily, oral per cycle. | Drug: LY2452473<br>* LY2452473 is a selective androgen receptor modulator which is agonist on the muscle but which spares the prostate.<br>* Other names: Selective Androgen Receptor Modulator;|
| Active Comparator: LY2452473 Dose 3<br>Subjects who meet the eligibility criteria, will be randomized, to either placebo, LY SARM Dose 1, LY SARM Dose 2 or LY SARM Dose 3 daily, oral per cycle. | Drug: LY2452473<br>* LY2452473 is a selective androgen receptor modulator which is agonist on the muscle but which spares the prostate.<br>* Other names: Selective Androgen Receptor Modulator;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sexual Activity Score of Psychosexual Daily Questionnaire (PDQ-4) | The primary outcome is change in sexual activity score, assessed by the Psychosexual Daily Questionnaire (PDQ). The questionnaire covered 3 different domains: 1) sexual desire, enjoyment, and performance; 2) sexual activity score; and 3) mood. Sexual activity was assessed using a checklist format (12-item) and the score range of 0 to 12 with higher scores representing better sexual activity. | 12 weeks from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in All Domains of International Index of Erectile Function (IIEF) | IIEF is a validated, 15-item questionnaire that assesses 5 domains of sexual function: erectile function (range 1-30), orgasmic function (range 0-10), sexual desire (range 2-10), intercourse satisfaction (range 0-15), and overall sexual satisfaction (range 2-10). Each question was answered on a 6-point or 5-point scale from 0/1 to 5 (best) with a total possible score (sum of 5 domains) range of 5 to 75 with higher scores representing better function. | 12 weeks from baseline | 
| Change in Sexual Activity, Interest, and Desire Scale (SAID) | The Sexual Activity, Interest, and Desire Scale (SAID) is an 8-item questionnaire that evaluates 3 response domains, including sexual thinking, sexual arousal, and sexual activity. The score was linearly transformed to a 0 to 100 scale for each item. The average score ranges 0-100. The higher the score, the better the sexual function. | 12 weeks from baseline | 
| Change in Derogatis Index of Sexual Function Male II (DISF-M-II) | Derogatis Index of Sexual Function Male II (DISF-M-II) is a 25-item questionnaire that provides an estimate of perceived quality of sexual activities in 5 response domains: sexual desire/drive (range 0-33), sexual arousal (range 0-33), sexual activity (range 0-35), orgasm (range 0-26), and sexual satisfaction/partner relationship (range 0-25). The total possible score (sum of 5 domains) range of 0 to 152 with higher scores representing better function. | 12 weeks from baseline | 
| Change in Three Domains of Men's Sexual Health Questionnaire (MSHQ) | Men's Sexual Health Questionnaire (MSHQ), a 25-item questionnaire, assesses sexual function and satisfaction. It consists 5 domains: Erection (3 items, ranging from 0 to 15 (best)), Ejaculation (7 items, ranging from 1 to 35 (best)), Satisfaction (6 items, ranging from 6 to 30 (best)), Sexual desire (4 items, ranging 4-20 (best)), and Sexual activity (3 items, ranging 3-15 (best)). Erection, Ejaculation and Satisfaction domains were measured and the higher score representing better sexual function and satisfaction. | 12 weeks from baseline | 
| Change in Two Domains of Expanded Prostate Cancer Index Composite (EPIC) | Expanded Prostate Cancer Index Composite (EPIC) is a 50-item, comprehensive instrument designed to evaluate patient function and bother after prostate cancer treatment. Of its four domains, the sexual domain (range 0-100) and hormonal domain (range 0-100) were utilized. The response for each item is standardized to a 0 to 100 scale. Higher score yields better quality of life. | 12 weeks from baseline | 
| Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale | The FACIT Fatigue Scale is a 13-item questionnaire that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four-point scale (4 = not at all fatigued to 0 = very much fatigued). Score ranges 0-52. The higher the score, the better the quality of life. | 12 weeks from baseline | 
| Change in Hypogonadism Energy Diary (HED) | Hypogonadism Energy Diary (HED) is a 4-item questionnaire that intended to assess real-time energy levels. Score ranges 0 to100 with higher scores representing higher energy. each question uses an 11-point numerical rating scale (0-10) with 10 corresponding to full of energy or extreme tiredness. HED score was the average of the scores for these 4 items. Scores were linearly transformed to a 0 to 100 scale. Higher scores representing higher energy. | 12 weeks from baseline | 
| Change in International Prostate Symptom Score (IPSS) | International Prostate Symptom Score (IPSS) is a 8-item, extensively validated and widely used self-reported measure of lower urinary tract symptoms questionnaire. It includes Urinary Symptoms (item1-7, range 0-35) and Quality of Life Due to Urinary Symptoms (item 8, range 0-6). The higher the score, the severer of the urinary symptoms and worse quality of life due to symptoms. | 12 weeks from baseline | 
| Change in Positive and Negative Affect Scale (PANAS) | The Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire that consists of two 10-item scales to measure both positive and negative affect. Each item is rated on a 5-point scale of 1 (very slightly or not at all) to 5 (extremely). Score ranges 10-50 for both positive and negative affect. The higher scores represent higher levels of positive/negative affect. | 12 weeks from baseline | 
| Change in Body Mass Using DXA | Whole body, appendicular, and trunk lean mass were measured using dual energy X- ray absorptiometry (DXA), calibrated using a soft tissue phantom before each scan. | 12 weeks from baseline | 
| Change of Maximal Voluntary Muscle Strength | The maximal voluntary muscle strength was measured in the leg press exercise using the 1-repetition method | 12 weeks from baseline | 
| Change in Gait Speed in 6-minute Walk | Tests of Physical Function and Task-Specific Performance measured by gait speed in 6-min walk | 12 weeks from baseline | 
| Change of 50 Meters Walk Tests- Unloaded /Loaded | Tests of Physical Function and Task-Specific Performance measured by 50-meter timed walk + 20% load carry. Physical Function was evaluated using test of 50-meter loaded walking speed. One test consisted of walking 50 meters as rapidly as possible without running (unloaded) while the second test required participants to carry a load equivalent to 20% of their baseline body weight evenly distributed in two canvas tote bags(loaded). Time was measured electronically with a digital clock. Speed in meters per second is calculated by the following: 50/time. | 12 weeks from baseline | 
| Change in Power of Stair Climbing Tests- Unloaded/Loaded | Tests of Physical Function and Task-Specific Performance measured by Stair-climbing power +/- 20% load carry. Physical Function was evaluated using two tests of stair climb power using an indoor 12-step staircase. One test consisted of ascending the 12-steps as rapidly as possible without running (unloaded stair climb) while the second test required participants to carry a load equivalent to 20% of their baseline body weight evenly distributed in two canvas tote bags (loaded stair climb). Time to ascend the stairs was measured electronically with a digital clock and switch mats placed at the base of the steps and on the 12th step. Power in watts is calculated by the following: [body weight (kilograms) * distance (meters)/ (time/60)] /6.12. | 12 weeks from baseline | 
| Change in Serum Total Testosterone Level | Serum total testosterone levels during screening was measured in the Quest Diagnostics Laboratory, Chantilly, VA, using liquid chromatography tandem mass spectrometry (LC-MS/MS) method certified by the Hormone Standardization Program for Testosterone (HoST) of the Centers for Disease Control and Prevention, Atlanta, Georgia. | 12 weeks from baseline | 
| Change in Free Testosterone Level | Free testosterone level for screening was measured using an equilibrium dialysis method. | 12 weeks from baseline | 
| Change in Serum Sex Hormone-binding Globulin (SHBG) Level | Serum SHBG level was measured using two-site directed immuno-chemiluminescence assays with sensitivity 2.5 nmol/L, and coefficients of variation less than 10% in low, medium and high range | 12 weeks from baseline | 
| Change in Serum Luteinizing Hormone (LH) Level | Serum LH level was measured using two-site directed immuno-chemiluminescence assays with sensitivity 0.1 U/L, and coefficients of variation less than 10% in low, medium and high range | 12 weeks from baseline | 
| Change in Estradiol Levels | Estradiol level was measured by LC-MS/MS. | 12 weeks from baseline | 
| Change of White Blood Cell | White Blood Cell was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Red Blood Cell | Red Blood Cell was measured for safety monitoring. | 12 weeks from baseline | 
| Change in Hematocrit | Hematocrit was measured for safety monitoring. | 12 weeks from baseline | 
| Change in Hemoglobin | Hemoglobin was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Mean Corpuscular Volume (MCV) | Mean corpuscular volume was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Red Blood Cell Distribution Width (RDW) | Red blood cell distribution width (RDW) was measured for safety monitoring. RDW was calculated with: standard deviation of the mean cell size divided by the mean corpuscular volume of the red cells multiplied by 100 | 12 weeks from baseline | 
| Change in Platelet Count | Platelet count was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Aspartate Aminotransferase (AST) | Aspartate aminotransferase was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Alanine Aminotransferase (ALT) | Alanine aminotransferase was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Total Bilirubin | Total Bilirubin was measured for safety monitoring. | 12 weeks from baseline | 
| Change in Serum Alkaline Phosphatase | Serum alkaline phosphatase was measured for safety monitoring. | 12 weeks from baseline | 
| Change of Lipid Panel | Plasma lipids were measured for safety monitoring. | 12 weeks from baseline | 
| Change in Fasting Glucose Levels | Glucose will be measured in a fasting serum sample at Quest Lab. | 12 weeks from baseline | 
| Change in Insulin | Insulin will be measured using an immunoassay at Quest lab. | 12 weeks from baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate Cancer