A selective Androgen Receptor Modulator for Symptom Management in Prostate Cancer

描述（由申请人提供）：前列腺癌患者生存率的提高已经将人们的注意力集中在治疗对生活质量的影响上，特别是对性症状、身体功能障碍和疲劳的影响，这些都是导致生活质量差的重要因素。雄激素缺乏是常见的，也是这些症状的一个重要的可补救因素；然而，对于有前列腺癌病史的男性使用睾酮替代疗法的风险的不确定性，使得医生不愿使用睾酮，即使是那些在根治性前列腺切除术后被认为已经治愈的男性。一种新的选择性雄激素受体调节剂- LY SARM -是理想的缓解雄激素缺乏症状和减轻与睾酮治疗相关的疾病复发的担忧，因为它作为雄激素激动剂作用于肌肉，骨骼和性功能，但作为拮抗剂作用于前列腺。我们的目的是开展一项分阶段、双盲、安慰剂对照、剂量反应研究，以确定LY SARM在改善因器官局限性前列腺癌接受根治性前列腺切除术、复发风险较低、雄激素缺乏的前列腺癌患者的性症状、疲劳和身体功能障碍方面的有效性和安全性。在第一阶段，10名受试者将随机接受安慰剂或1mg剂量。如果没有观察到安全信号，额外的受试者将被随机分配到0,1或5mg剂量。我们的第一个目标是比较0、1或5毫克LY SARM在因器官局限性前列腺癌接受根治性前列腺切除术、有雄激素缺乏症和性功能（性活动评分、性欲、勃起功能、痛苦和性生活质量）的男性中的作用。第二个目的是比较0、1或5毫克SARM对疲劳、健康和情感平衡以及疾病特异性生活质量的影响。我们的第三个目的是确定SARM是否比安慰剂更能改善肌肉质量和力量、身体功能和有氧能力。男性b>9岁，接受根治性前列腺切除术治疗器官局限性癌（pT2,N0,M0）， Gleason评分<6，根治性前列腺切除术后b> 2年未检测到PSA (<0.1 ng/mL)，性功能障碍，疲劳或身体功能障碍症状，总睾酮（<300 ng/dL）和/或游离睾酮<60 pg/ mL，将随机分配到每天0,1或5 mg LY SARM，持续3个月。结果包括性症状（性活动评分、性欲、勃起功能、性困扰、性生活质量）、情感平衡、情绪、疲劳、疾病特异性生活质量、身体功能、肌肉力量和有氧能力（VO2max、VO2峰值、乳酸阈值）的变化。我们将监测红细胞压积，PSA和生化复发，定义为“PSA为>0.2 ng/mL，确认水平>0.2 ng/mL”。仔细选择复发风险极低的受试者，严格的安全监测，明确的停药规则，独立的DSMB，选择有症状的低睾酮男性，以及良好的试验设计（块随机化，安慰剂对照，盲法）将最大限度地提高该SARM试验在非常需要的患者群体中的成功结果的机会。

DESCRIPTION (provided by applicant): Improved survival of men with prostate cancer has focused attention on the impact of treatment on quality of life, especially on sexual symptoms, physical dysfunction, and fatigue, which are important contributors to poor quality of life. Androgen deficiency is common and an important remediable contributor to these symptoms; however, uncertainty about the risk of testosterone replacement in men with a history of prostate cancer has rendered physicians reticent to use testosterone even in men who are deemed cured after a radical prostatectomy. A novel selective androgen receptor modulator - LY SARM - is ideal for alleviating symptoms of androgen deficiency and mitigating concerns about disease recurrence associated with testosterone therapy because it acts as an androgen agonist on the muscle, bone, and sexual function, but as an antagonist on the prostate. Our objective is to conduct a staged, double-blind, placebo-controlled, dose response study to determine the efficacy and safety of LY SARM in improving sexual symptoms, fatigue, and physical dysfunction in men with prostate cancer who have undergone radical prostatectomy for organ-localized prostate cancer, are deemed to be at low risk of recurrence, and who have androgen deficiency. In stage 1, 10 subjects will be randomized to either placebo or 1 mg dose. If no safety signal is observed, additional subjects will be randomized to 0, 1 or 5 mg dose. Our first aim is to compare 0, 1 or 5 mg of LY SARM in men, who have undergone radical prostatectomy for organ-localized prostate cancer, have symptomatic androgen deficiency, and with regard to sexual function (sexual activity score, sexual desire, erectile function, distress ad sexual life quality). The second aim is to compare the effects of 0, 1 or 5 mg of SARM on fatigue, well-being and affectivity balance, and disease-specific quality of life. Our third aim isto determine whether SARM administration improves muscle mass and strength, physical function, and aerobic capacity more than placebo. Men >19-years, who have undergone radical prostatectomy for organ-localized cancer (pT2,N0,M0), Gleason score <6, undetectable PSA (<0.1 ng/mL) for >2 years after radical prostatectomy and symptoms of sexual dysfunction, fatigue, or physical dysfunction, and low total (<300 ng/dL) and/or free testosterone <60 pg/ml, will be randomized to 0, 1 or 5 mg LY SARM daily for 3 months. Outcomes include changes in sexual symptoms (sexual activity score, sexual desire, erectile function, sexual distress, sexual life quality), affectivity balance, mood, fatigue, disease-specific quality of life, measures of physical function, muscle strength, and aerobic capacity (VO2max , VO2 peak, lactate threshold). We will monitor hematocrit, PSA, and biochemical recurrence, defined as "PSA of >0.2 ng/mL with a confirmatory level of >0.2 ng/mL". Careful selection of subjects with very low risk of recurrence, rigorous safety monitoring, clear stopping rules, an independent DSMB, selection of symptomatic men with low testosterone, and good trial design (block randomization, placebo-controlled, blinded) will maximize the chances of successful outcome of this SARM trial in a very needy patient population.