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

优化 [18F]FTT 的放射合成产量以实现广泛分布

基本信息

批准号：
10253555
负责人：
Hsiaoju Sharon Lee
金额：
$ 39.01万
依托单位：
TREVARX BIOMEDICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10253555
关键词：
Academia Address Applications Grants Binding Biological Assay Breast Cancer Center Cancer Patient Chemistry Clinical Clinical Trials Consumption Data Development Drug Approval Gene Mutation Genes Genomics Goals Grant High Pressure Liquid Chromatography Image Label Lead Malignant Neoplasms Malignant neoplasm of ovary Measures Methods Multi-Institutional Clinical Trial Multicenter Trials Mutation Ovarian Patients Pennsylvania Pharmaceutical Preparations Phase Phase II Clinical Trials Poly(ADP-ribose) Polymerases Positron-Emission Tomography Production Prostate Publishing Radiolabeled Radiopharmaceuticals Research Route Site Small Business Technology Transfer Research Solid Sterility System Testing Time Tracer Training Translations Universities Washington Work analog anticancer research base cancer therapy clinical translation commercialization companion diagnostics early phase clinical trial feasibility testing first-in-human imaging agent in vivo inhibitor/antagonist malignant breast neoplasm neoplastic cell novel therapeutics phase III trial predictive marker programs quantitative imaging repaired targeted treatment tumor uptake

项目摘要

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.

抽象的：聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi's）已成为重要的新型治疗药物针对乳腺癌、卵巢癌、前列腺癌和许多其他癌症中存在的一系列基因突变。这些药物针对的是具有 BRCA 相关基因突变的患者和药物/或肿瘤，但并非所有患者同样重要的是，这种方法忽略了具有这些突变的患者。可能会受益于 PARPi，因为没有 BRCA 相关基因的肿瘤可能会做出反应。 (Trevarx) 第一个许可产品 [18F]florthanatrace ([18F]FTT) 是 PARPi rucaparib 的 PET 标记类似物，并提供卵巢和乳腺区域 PARP 表达的定量图像。宾夕法尼亚大学 (Penn)、圣路易斯华盛顿大学 (WU) 和马里兰州进行癌症治疗安德森癌症中心 (MDACC) 支持 [18F]FTT 肿瘤摄取作为体内测量的准确性区域 PARP1 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成果，比其他竞争对手领先 2-3 年 PET PARPi 显像剂最近刚刚完成首次人体研究。 Trevarx 的目标是使 [18F]FTT 广泛用于临床，作为 PARPi 的伴随诊断 Trevarx 与 MDACC、宾夕法尼亚大学和 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 [18F]FTT NDA 为了支持这一目标， Trevarx 必须开发经过验证的 GMP 合成和 [18F]FTT 测试，以支持最终的 Trevarx 和 NDA 提交的第一阶段 STTR 提案的商业生产。 Penn 将通过最大化产物来确定合成 [18F]FTT 的最佳方法以进行广泛分发一致性和生产收率，目标如下： (1) 评估合成收率和产量使用两种常见的符合 GMP 的化学模块通过两种不同的合成路线实现 [18F]FTT 的稳健性； (2)测试使用固相萃取完成法简化[18F]FTT纯化的可行性。这些目标将产生一个优化的合成平台，该平台将导致第二阶段 STTR 的努力，以推出培训和合规计划，以参加 2 期临床试验并开发 [18F]FTT 与商业 PET 放射性药物供应合作伙伴一起生产，以确保示踪剂供应广泛可用进行3期多中心试验并在药物批准后立即进行临床推广。