Prostate Specific Anti-androgen Therapy for Localized Prostate Cancer

前列腺特异性抗雄激素疗法治疗局限性前列腺癌

基本信息

批准号：
10760194
负责人：
Maithili Rairkar
金额：
$ 40.57万
依托单位：
ALESSA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760194
关键词：
Accounting Address Adjuvant Androgen Antagonists Animals Antiandrogen Therapy Anxiety Autopsy Bicalutamide Biological Assay Biopsy Canis familiaris Cell Line Cells Characteristics Clinical Clinical Trials Collaborations Community Practice Data Development Disease Disease Progression Dose Dropout Evaluation Formulation Fright Generations Goals Histopathology Human Image Implant Impotence Incidence Infiltration Inflammation LNCaP Lead Libido Local Therapy Longitudinal Studies Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Metabolic syndrome Metastatic Prostate Cancer Modeling Monitor Mus Nature Operative Surgical Procedures Oral Patients Pharmaceutical Preparations Pharmacologic Substance Phase Plasma Polymers Preclinical Testing Preparation Prostate Prostatectomy Radiation Radiation therapy Radical Prostatectomy Rattus Residual state Risk Safety Seed Implantation Sex Functioning Small Business Innovation Research Grant Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Sterility Sterilization Structure Testing Therapeutic Tissues Uncertainty Urinary Incontinence Visit anticancer activity biocompatible polymer bone mass cancer diagnosis cancer therapy clinic ready clinical development cohort commercialization comparative cost design drug distribution efficacious intervention enzalutamide experience high risk hormone therapy in vivo in vivo evaluation industry partner innovation irradiation lead candidate lead optimization manufacture melting men minimally invasive muscle form novel novel therapeutic intervention pharmacokinetics and pharmacodynamics practice setting pre-clinical preclinical study product development prostate biopsy prostate cancer progression prototype public health relevance response screening side effect technology platform

项目摘要

Abstract Prostate cancer is the most common malignancy in men worldwide and its incidence is steadily rising. Treatment options for early-stage prostate cancer include radical prostatectomy, prostate irradiation, or active surveillance. Systemic anti-androgen hormonal therapy is offered to high-risk patients in combination with radiation therapy and in men with advanced or metastatic prostate cancer. Promising data from the ENACT trial has suggested that hormonal therapy with a second-generation anti-androgen, enzalutamide, may benefit men on active surveillance. Daily oral enzalutamide for one year reduced the rate of prostate cancer progression but came at the cost of considerable systemic side effects. Thus, there is an unmet need as well as an opportunity to define novel therapeutic strategies for early-stage prostate cancer. We propose to address this unmet need by developing polymer-based drug loaded seed implants. These seed will be surgically placed into the prostate with the goal to provide sustained anti-androgen therapy while minimizing systemic side effects. In extensive preclinical testing and clinical proof of principle studies, we have shown that we can deliver short- term therapeutic doses of bicalutamide pre-prostatectomy and in combination with radiation therapy. Leveraging our prior experience, we therefore propose to develop a long-term drug delivering seed implant containing a second-generation anti-androgen for men with early-stage prostate cancer on active surveillance. The optimal seed implant would deliver therapeutic drug levels selectively to the prostate gland for at least two years and will be inserted via a minimally invasive surgery performed in a community practice setting. In two aims we propose in Aim 1 to develop an optimized lead implant formulation of each of the three approved 2nd-generation antiandrogens (enzalutamide, apalutamide and darolutamide) and in Aim 2 to evaluate these seed implants in a short-term feasibility in vivo rat study (Aim 2a) and a long-term in vivo rat study to determine the pharmacokinetic and pharmacodynamic profile of seed implant formulations (Aim 2b) when deployed into the rat prostate. The first, short-term, 2-week study will include three cohorts of optimized lead seed implant formulations containing enzalutamide, apalutamide and darolutamide and one control cohort with a bicalutamide implant to evaluate safety, feasibility, and short-term PK profiles in prostate, plasma, and other tissues. The long- term study with the same four cohorts will evaluate drug distribution across the prostate, anti-androgen tissue effects, and residual drug content in recovered seed implants to estimate cumulative drug elution at 2, 4 and 6 months. All implants will be designed for easy surgical insertion. This data will allow the selection of the most promising seed implants to advance to further IND-enabling studies for Ph1 clinical trials in men with early-stage prostate cancer and initiate collaborations with industry partners for clinical development and commercialization.

抽象的前列腺癌是全世界男性最常见的恶性肿瘤，其发病率正在稳步上升。治疗早期前列腺癌的选择包括根治性前列腺切除术、前列腺放疗或主动监测。为高危患者提供全身抗雄激素激素治疗并结合放射治疗以及患有晚期或转移性前列腺癌的男性。 ENACT 试验的有希望的数据表明第二代抗雄激素恩杂鲁胺的激素疗法可能有益于积极主动的男性监视。一年内每日口服恩杂鲁胺可降低前列腺癌进展率，但结果是相当大的系统性副作用的代价。因此，存在未满足的需求以及定义的机会早期前列腺癌的新治疗策略。我们建议通过以下方式解决这一未满足的需求开发基于聚合物的载药种子植入物。这些种子将通过手术植入前列腺目标是提供持续的抗雄激素治疗，同时最大限度地减少全身副作用。在广泛的临床前测试和原理研究的临床证明中，我们已经证明我们可以提供短期的前列腺切除术前和与放射治疗相结合的比卡鲁胺的长期治疗剂量。杠杆作用根据我们之前的经验，我们因此建议开发一种长期药物输送种子植入物，其中含有用于主动监测的早期前列腺癌男性的第二代抗雄激素药物。最优的种子植入将选择性地将治疗药物水平输送到前列腺至少两年，并且将通过在社区实践环境中进行的微创手术插入。我们在目标 1 中提出了两个目标，即为三种已批准的药物中的每一种开发一种优化的先导植入物配方。第二代抗雄激素（恩杂鲁胺、阿帕鲁胺和达洛鲁胺）并在目标 2 中评估这些药物在短期体内大鼠研究（目标 2a）和长期体内大鼠研究中确定种子植入的可行性种子植入制剂的药代动力学和药效学特征（目标 2b）部署到大鼠前列腺。第一项为期两周的短期研究将包括三组优化的铅种子植入含有恩杂鲁胺、阿帕鲁胺和达洛鲁胺的制剂以及含有比卡鲁胺的对照组植入物以评估前列腺、血浆和其他组织中的安全性、可行性和短期 PK 曲线。长- 相同四个队列的短期研究将评估药物在前列腺、抗雄激素组织中的分布效果和回收的种子植入物中的残留药物含量，以估计 2、4 和 6 时的累积药物洗脱几个月。所有种植体的设计都易于手术插入。该数据将允许选择最有希望的种子植入物将进一步推进针对早期男性的 1 期临床试验的 IND 研究前列腺癌，并与行业合作伙伴开展临床开发和商业化合作。