Breast Cancer PARP PET Imaging AIP to Support FDA Approval & Commercialization

摘要： 聚(ADP-核糖)聚合酶(PARP)抑制剂药物(PARPI‘s)已成为重要的新疗法 针对乳腺、卵巢、前列腺和许多其他组织中广泛存在的基因突变的药物 癌症。识别可能受益于PARPI的患者依赖于同源基因缺陷的分析 重组(HRD)，如BRCA1/2突变，但这些检测一直不能完美地预测应答 肿瘤细胞中存在的与PARP1的药物结合是有效的PARPI的一个共同和必要的因素 心理治疗。[18F]氟乙醇(FTT)是一种PET标记的PARPI rucaparib的类似物，早期临床数据显示 卵巢癌和乳腺癌试验支持将[18F]FTT肿瘤摄取作为局部PARP1药物的体内测量 结合，并表明[18F]FTT PET作为PARPI预测成像生物标记物的潜力。[18F]FTT可以 因此，通过确定最有可能有反应的患者，为乳腺癌和其他癌症患者提供好处 接受PARPI治疗，同时避免那些因毒性、不必要的费用和浪费而不起作用的人 时间到了。 为了进一步推动[18F]FTT的开发、临床翻译和商业化，我们提出了一种学术 由宾夕法尼亚大学((Penn)，马里兰州首席学术合作伙伴)组成的产业伙伴(AIP) 安德森癌症中心(MDACC)和华盛顿大学(吴)与Trevarx Biomedical，Inc.(Trevarx)。 Trevarx是一家拥有[18F]FTT独家许可证的放射性制药公司，正在将[18F]FTT作为一种 指导PARPI治疗的成像生物标记物，在乳腺癌中是第一个适应症。基于与以下方面的讨论 FDA和Advisors，[18F]FTT批准将要求对[18F]FTT PET/CT的准确性进行第三阶段研究 PARP1表达癌的诊断。本AIP提案的目标集中在以下关键组件上 FDA批准[18F]FTT的3期试验：(1)Trevarx持有的标准化示踪剂生产的IND 方法和产品规格；(2)PARP1免疫组织化学(IHC)分析的验证 福尔马林固定石蜡包埋(FFPE)组织中的表达作为[18F]FTT PET的参考标准 诊断准确性；以及(3)在多中心环境中测试和验证方法的第二阶段多中心试验 并为设计关键的三期试验提供了初步数据。完成这些目标将使一个阶段 3支持[18F]FTT FDA批准的试验，[18F]FTT的商业供应，以及学术机构正在进行的研究 合作伙伴记录[18F]FTT PET/CT在指导PARPI治疗方面的价值，包括预期的多 以生物标记物为中心的研究。

Abstract: Poly (ADP-ribose) polymerase (PARP) inhibitor drugs (PARPi's) have emerged as important new therapeutic agents targeting a broadening class of gene mutations present in breast, ovarian, prostate and a host of other cancers. Identification of patients who might benefit from PARPi's has relied on assays for defects in homologous recombination (HRD), such as BRCA1/2 mutations, but these assays have been imperfect predictors of response to PARPi's. Drug binding to PARP1 present in tumor cells is a common and necessary factor for effective PARPi therapy. [18F]fluorthanatrace (FTT) is a PET-labeled analog of the PARPi rucaparib, and early clinical data in ovarian and breast cancer trials support [18F]FTT tumor uptake as an in-vivo measure of regional PARP1 drug binding, and indicate the potential of [18F]FTT PET as a PARPi predictive imaging biomarker. [18F]FTT could therefore provide benefits for patients with breast and other cancers by identifying those most likely to respond to PARPi therapy, while sparing those who will not respond from toxicity, unnecessary expense, and wasted time. To further the development, clinical translation, and commercialization of [18F]FTT, we propose an Academic Industrial Partnership (AIP) comprised of The University of Pennsylvania ((Penn), lead academic partner), MD Anderson Cancer Center(MDACC), and Washington University (WU) with Trevarx Biomedical, Inc (Trevarx). Trevarx, a radiopharmaceutical corporation with the exclusive license for [18F]FTT, is developing [18F]FTT as an imaging biomarker to guide PARPi treatment, with a first indication in breast cancer. Based on discussions with the FDA and advisors, [18F]FTT approval will require a Phase 3 study of the accuracy of [18F]FTT PET/CT for diagnosing PARP1 expressing cancer. The aims of this AIP proposal focus on critical components necessary for a Phase 3 trial for [18F]FTT FDA approval: (1) a Trevarx-held IND with standardized tracer production methodology and product specification; (2) validation of an immunohistochemistry (IHC) assay of PARP1 expression in formalin-fixed paraffin embedded (FFPE) tissue as a reference standard for [18F]FTT PET diagnostic accuracy; and (3) a Phase 2 multi-center trial to test and validate methods in a multi-center setting and provide preliminary data to design the pivotal Phase 3 trial. Completion of the these aims will enable a Phase 3 trial to support [18F]FTT FDA approval, commercial supply of [18F]FTT, and ongoing research by the academic partners to document the value of [18F]FTT PET/CT for guiding PARPi treatment, including prospective multi- center biomarker-focused studies.