Optimizing Radiosynthetic Yield of [18F]FTT For Wide-Spread Distribution

摘要： 聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi's）已成为重要的新型治疗剂 针对乳腺癌、卵巢癌、前列腺癌和其他癌症中存在的更广泛的基因突变。 这些药物已针对BRCA相关基因突变的患者和/或肿瘤，但并非所有患者 他们的肿瘤对PARPi有反应同样重要的是，这种方法忽略了那些 可能受益于PARPi，因为没有BRCA相关基因的肿瘤可能会产生反应。Trevarx Biomedical Inc. S （Trevarx）的第一个许可产品，[18 F]fluorthanatrace（[18 F]FTT），是PARPi rucaparib的PET标记的类似物， 并提供局部PARP表达的定量图像。卵巢和乳腺的早期临床试验数据 在宾夕法尼亚大学（Penn）、圣路易斯的华盛顿大学（WU）和MD 安德森癌症中心（MDACC）支持[18 F]FTT肿瘤摄取作为体内测量的准确性。 区域PARP 1药物结合，并表明其作为更有效的PARPi成像预测生物标志物的潜力。 [18F]FTT拥有已发表的学术研究的成熟机构，并领先于其他竞争对手2-3年。 PET PARPi成像剂最近才完成首次人体研究。 Trevarx的目标是使[18 F]FTT广泛用于临床，作为PARPi的伴随诊断 疗法Trevarx与MDACC，Penn和WU合作，正在开发一项2期多中心临床试验， 乳腺癌，将导致随后的3期试验，以支持[18 F]FTT NDA。为了支持这一目标， Trevarx必须开发支持最终[18 F]FTT所需的经验证的GMP合成和测试 用于3期试验和NDA提交的商业化生产。Trevarx的第一阶段STTR提案， Penn将确定合成[18 F]FTT的最佳方法，通过最大化产品 一致性和生产收率，目的如下：（1）评价合成收率和生产 通过两种不同的合成路线使用两种通用GMP合规化学模块的[18 F]FTT的稳健性; 和（2）测试使用固相萃取方法简化[18F]FTT纯化的可行性。完成 这些目标将导致一个优化的综合平台，这将导致第二阶段STTR的努力，推出一个 针对将参与II期临床试验并开发[18 F]FTT的研究中心的培训和合规性计划 与商业PET放射性药物供应合作伙伴一起生产，以确保广泛可用的示踪剂供应 用于3期多中心试验，并在药物批准后迅速进行临床推广。

ABSTRACT: Poly (ADP-ribose) polymerase (PARP) inhibitors (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. These drugs have been targeted to patients and/or tumors with BRCA-related gene mutations, but not all patients whose tumors have these mutations respond to PARPi. Equally important, this approach misses patients who may benefit from PARPi since tumors without BRCA-related genes may respond. Trevarx Biomedical Inc.’s (Trevarx) first licensed product, [18F]fluorthanatrace ([18F]FTT), is a PET-labeled analog of the PARPi rucaparib, and provides quantitative images of regional PARP expression. Early clinical trial data in ovarian and breast cancer carried out at the University of Pennsylvania (Penn), Washington University in St. Louis (WU) and MD Anderson Cancer Center (MDACC) support the accuracy of [18F]FTT tumor uptake as an in-vivo measure of regional PARP1 drug binding and indicate its potential as a more effective PARPi imaging predictive biomarker. [18F]FTT has an established body of published academic research and a 2-3 year lead over other competitive PET PARPi imaging agents that have only recently completed first-in-human studies. Trevarx has the goal of making [18F]FTT widely available for clinical use as a companion diagnostic for PARPi therapy. Partnering with MDACC, Penn, and WU, Trevarx is developing a Phase 2 multi-center clinical trial in breast cancer that will lead to a subsequent Phase 3 trial to support an [18F]FTT NDA. To support this goal, Trevarx must develop the validated GMP synthesis and testing for [18F]FTT that is required to support eventual commercial production for Phase 3 trials and NDA submission. This Phase 1 STTR proposal by Trevarx and Penn will determine the best method for synthesizing [18F]FTT for widespread distribution by maximizing product consistency and production yield with the following aims: (1) Evaluate the synthesis yield and production robustness of [18F]FTT using two common GMP-compliant chemistry modules via two different synthesis routes; and (2) test the feasibility of simplifying [18F]FTT purification using solid-phase extraction methods. Completion of these aims will result in an optimized synthesis platform that will lead to a Phase 2 STTR effort to roll out a training and compliance program to sites that will participate in Phase 2 clinical trials and develop [18F]FTT for production with a commercial PET radiopharmaceutical supply partner to assure broadly available tracer supply for Phase 3 multi-center trials and prompt clinical rollout after drug approval.