High-dose Testosterone in Men with Metastatic Castration-resistant Prostate Cancer and ATM or CDK12 deficiency

高剂量睾酮治疗患有转移性去势抵抗性前列腺癌且 ATM 或 CDK12 缺乏症的男性

• 批准号: 10260977
• 负责人: Bruce Montgomery
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260977
• 关键词: Address; Adverse event; Androgen Therapy; Androgens; Biological Markers; Cancer Etiology; Cancer Patient; Cessation of life; Clinical; Cohort Studies; Common Terminology Criteria for Adverse Events; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Gene; DNA Repair Pathway; Decision Making; Diagnostic radiologic examination; Disease; Dose; Fred Hutchinson Cancer Research Center; Future; Genes; Genomic Instability; Genomics; Immunotherapy; Incidence; Individual; International; Intramuscular Injections; Length; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Mutation; Older Population; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Population; Progression-Free Survivals; Quality of life; Resistance; Safety; Severities; Subgroup; Surveys; Survival Rate; Testing; Testosterone; Therapeutic; Toxic effect; Universities; Veterans; Washington; Work; advanced prostate cancer; arm; base; bipolar patients; castration resistant prostate cancer; deprivation; design; early detection biomarkers; effective therapy; effectiveness testing; efficacy evaluation; homologous recombination; improved; indexing; men; neoplastic cell; patient population; patient subsets; personalized care; phase 2 study; potential biomarker; predicting response; predictive marker; primary endpoint; response; response biomarker; secondary endpoint; sound; study population; tumor; working group

Abstract Advanced prostate cancer is a universally lethal disease and one for which no biomarkers have yet been found to inform therapeutic decision making. DNA repair deficiency in the homologous recombination and CDK12 pathways increases sensitivity of tumors to the DNA damaging effects of high dose testosterone based on early biomarker interrogations of phase II high dose testosterone studies. High dose testosterone is also very well tolerated in appropriately selected patient populations who are asymptomatic. The proposed study is a two arm phase II study of high dose testosterone in men with metastatic, castration resistant prostate cancer containing mutations in ATM or CDK12. Patients would receive intermittent high dose testosterone (intramuscular injections Day 1 of each monthly cycle) until clinical or radiographic progression or intolerance. Androgen deprivation is continued in order to maintain consistent nadir testosterone levels which are critical to the concept of inducing genomic instability by exposing tumor cells to very high and low testosterone levels over the length of the cycle. The primary endpoint will be 50% decline in PSA from baseline. Secondary endpoints are radiographic response per RECIST, radiographic progression free survival, PSA progression free survival, overall survival, PSA50 response rate in each genomic subgroup, quality of life by FACT-P and International Index of Erectile Function (IIEF) surveys and incidence and severity of adverse events according to CTCAE version 4.0. This study will provide critical information regarding efficacy and toxicity of high dose testosterone therapy in a biomarker selected population. High dose testosterone in appropriately selected patients is very well tolerated and would provide treatment options for patients who are otherwise not at the appropriate point in their treatment sequence for other treatments. The importance of this study will be to establish the utility of DNA repair deficiency in specific genes as a predictive biomarker for response to high dose testosterone and to justify larger studies targeting specific subsets, particularly for subsets for which effective therapies have not yet been established such as ATM and CDK12.

摘要 晚期前列腺癌是一种普遍致命的疾病，目前还没有发现其生物标志物。 为治疗决策提供信息。同源重组与CDK12的DNA修复缺陷 通路增加肿瘤对高剂量睾酮DNA损伤效应的敏感性 第二阶段高剂量睾酮研究的早期生物标记物询问。高剂量的睾丸素也非常 在适当选择的无症状患者群体中耐受性良好。建议的研究是一项 抗去势转移性前列腺癌患者大剂量睾酮的双臂II期研究 含有ATM或CDK12突变的。患者将接受间歇性高剂量睾丸素 (每个月周期的第一天肌肉注射)，直到临床或放射学进展或不耐受。 继续剥夺雄激素是为了维持一致的低谷睾酮水平，这对 通过将肿瘤细胞暴露在非常高和很低的睾酮水平来诱导基因组不稳定的概念 在周期的长度上。主要终点将是PSA较基准下降50%。次要的 终点是RECIST的放射治疗反应、放射治疗无进展存活率、PSA进展 自由存活率、总存活率、各基因组亚组的PSA50应答率、FACT-P和 国际勃起功能指数(IIEF)调查以及不良事件的发生率和严重性 至CTCAE 4.0版。这项研究将提供有关高剂量的疗效和毒性的关键信息。 在生物标记物选择的人群中进行睾酮治疗。适当选择大剂量睾酮 患者的耐受性很好，将为原本不在 在他们的治疗序列中适当的点用于其他治疗。这项研究的重要性将是 建立特定基因DNA修复缺陷作为高反应性反应的预测生物标志物的实用性 服用睾丸素并证明针对特定子集的更大规模研究的合理性，特别是针对 目前还没有建立有效的治疗方法，如ATM和CDK12。