A novel implantable drug-eluting device that delivers an anti-androgen to the prostate to treat localized early stage prostate cancer

摘要 前列腺癌（PCa）是男性最常见的癌症。在大多数男性中，疾病将留在 前列腺而不影响生存。尽管如此，每年仍有超过3万名男性死于前列腺癌，这表明 在治疗方案的改进方面存在明显的未满足需求。虽然早期前列腺癌是用 积极监测、前列腺切除术或前列腺放疗， 从激素治疗中获益。然而，这些治疗益处伴随着不期望的方面。 影响包括增加心血管疾病、代谢综合征、骨质疏松症的风险， 性欲和性功能。因此，辅助激素治疗的益处在以下男性中被抵消： 患有一种或多种共病，导致依从性差和不依从医生 建议.提供局部激素治疗的能力将提供一种新的策略， 辅助治疗而无额外的全身副作用。 为了解决这一未满足的需求，我们设计了一种新型的基于硅胶的植入式器械， 在前列腺中控制递送抗雄激素比卡鲁胺，同时使全身暴露最小化， 为可能因副作用而放弃激素治疗的男性提供一种可耐受的，有效的，长期的选择。 方面的影响.到目前为止，我们已经成功地测试了原型植入装置的概念证明和临床前研究 使用相关的小鼠和狗模型。使用植入物的关键因素包括安全性和最低限度 使用插入装置侵入性放置到受影响的前列腺肿瘤中。一种新型插入装置， 设计成能够将植入物无菌、可靠地转移到用于经会阴植入的手术工具上， 并且还用作植入物的初级包装。我们最初的设备原型需要量身定制， 计划接受前列腺放射治疗的男性的肿瘤中的特异性插入，目的是使 将多个植入物放置到肿瘤中，同时防止产量损失并满足制造规范。 我们计划与美国国家癌症研究所（NCI）合作进行首次人体研究，以测试局部的 激素类药物在接受放射治疗的早期前列腺癌患者中的应用到 为了促进这项研究，该应用程序将支持以下目标：1）重新设计和优化植入物 插入器械; 2）制造植入物/插入器械以支持临床研究; 3）进行试验 确认植入物和插入器械适合人类使用，维持放射治疗并建立 植入物产品的有效期。这些目标共同为FDA批准这一有前途的产品做好了准备， 临床可行性研究。参与该项目的团队在药物组合（药物- 设备）和药品开发，并已成功地将类似产品带到临床。 可行性研究的数据将确定该方法的安全性，并为随后的设计提供信息。 II期疗效研究，我们计划将植入物与主动监测进行比较。

Abstract Prostate cancer (PCa) is the most common cancer in men. In the majority of men, the disease will remain in the prostate and not impact survival. Nonetheless, over 30,000 men die from prostate cancer each year, indicating clear unmet need for improvements in treatment options. While early stage prostate cancer is treated with either active surveillance, prostatectomy or prostate radiation, higher risk unfavorable localized prostate cancer often benefits from the addition of hormonal therapy. However, these therapeutic benefits come with undesirable side effects including an increased risk of cardiovascular disease, metabolic syndrome, osteoporosis, and loss of libido and sexual function. As such, the benefits of adjuvant hormonal therapy are countervailed in men who have one or more comorbid conditions, leading to poor compliance and non-adherence to physician recommendations. The ability to provide localized hormonal therapy would provide a novel strategy to deliver adjuvant therapy without the additional systemic side effects. To address this unmet need, we have designed a novel silicone based implantable device with the goal of local, controlled delivery of an anti-androgen, bicalutamide, in the prostate while minimizing systemic exposure, to provide a tolerable, effective, long-term option for men who may otherwise forego hormonal therapy due to side effects. To date, we have successfully tested prototype implant devices in proof of concept and preclinical studies using relevant mouse and dog models. A critical element to the use of the implant involves safe and minimally invasive placement into the affected prostate tumor using an insertion device. A novel insertion device was designed to enable sterile, reliable transfer of the implant to surgical tools used for transperineal implantation, and also function as primary package for the implants. Our initial prototype of the device needs to be tailored for specific insertion into tumors from men planning to undergo prostate radiation, with the goals of enabling placement of multiple implants to tumors while preventing yield losses and meeting manufacturing specifications. We plan to conduct a first-in-human study in collaboration with the National Cancer Institute (NCI) to test localized hormonal drug delivery in men undergoing radiation therapy for unfavorable early stage prostate cancer. To facilitate this study, this application would support the following aims: 1) redesign and optimization of the implant insertion device; 2) manufacture of implants / insertion device to support the clinical study and; 3) conduct testing to confirm that implants and insertion devices are suitable for human use, sustain radiation therapy and establish the shelf life of the implant product. Together these aims ready this promising product for FDA-approval of the planned clinical feasibility study. The team working on this project is highly experienced in combination (drug- device) and pharmaceutical product development and has successfully brought similar products to the clinic. The data from the feasibility study will establish safety of the approach and inform the design of a subsequent Phase 2 efficacy study where we plan to compare the implant against active surveillance.