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：
10821733
负责人：
Hsiaoju Sharon Lee
金额：
$ 104.39万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10821733
关键词：
Binding Biological Assay Breast Cancer Patient Clinical Trials Cyclic GMP Databases Development Drug Formulations Drug Stability Ensure Formulation Foundations Gene Mutation Genes Genomics Image Industry Label Lead Malignant Neoplasms Malignant neoplasm of ovary Marketing Measures Methods Modeling Monitor Multi-Institutional Clinical Trial Multicenter Trials Ovarian Patient imaging Pennsylvania Performance Pharmaceutical Preparations Phase Phase III Clinical Trials Poly(ADP-ribose) Polymerase Inhibitor Polymerase Positron-Emission Tomography Preparation Procedures Process Production Prostate Proteins Radiolabeled Radiopharmaceuticals Reagent Recommendation Sampling Site Small Business Technology Transfer Research Specific qualifier value Standardization Technology Transfer Testing Tissues Tracer Translating Universities Writing analog clinical center clinical translation commercialization companion diagnostics design efficacy trial imaging biomarker improved in vivo inhibitor inhibitor therapy innovation malignant breast neoplasm novel performance site phase 2 study phase II trial phase III trial pre-Investigational New Drug meeting precision oncology predictive marker protein expression quantitative imaging radiotracer repaired response success supply chain targeted treatment timeline tumor uptake

项目摘要

ABSTRACT: Poly (ADP-ribose) polymerase inhibitors (PARPi’s) have emerged as important therapeutic agents targeting a broadening class of gene mutations approved for treatment of breast, ovarian, prostate, and other cancers. Genomic assays of BRCA-related genes and tumor homologous repair deficiency are used as companion diagnostics for PARPi therapy but have imperfect predictive efficacy for PARPi response. Trevarx Biomedical Inc.’s (Trevarx) product, [18F]Fluorthanatrace ([18F]FTT), a PET-radiolabeled analog of the PARPi, rucaparib, provides quantitative images of regional PARP expression and drug engagement for all approved PARPi’s. It can thus serve as a PARPi companion diagnostic to identify those most likely to respond to PARPi therapy, and importantly, those unlikely to respond. Over 175 patients imaged in single center clinical trials support the accuracy of [18F]FTT tumor uptake as an in-vivo measure of regional PARPi drug binding, and as an effective imaging-based biomarker of PARP-1 protein levels. A pre-IND meeting with FDA suggested that approval would require: (1) a Phase 3 tissue correlating [18F]FTT uptake and PARP-1 protein expression in tumor samples and (2) multi-center Phase 2 studies of [18F]FTT’s accuracy in predicting PARPi response. A 3-center Phase 2 trial PET-tissue comparison study has been initiated as a pilot for the larger Phase 3 trial, and striking new single- center Phase 2 results on [18F]FTT predictive accuracy strongly support Phase 2 multi-center trials under development. The focus of this proposal is to establish wide-spread radiopharmaceutical supply to support the expanded multi-center trials needed for approval and subsequent clinical translation. With a 3 year competitive lead, [18F]FTT is projected to enter a Phase 3 tracer-tissue trial and multi-center Phase 2 predictive efficacy trials to support an NDA in 2025. The steps described in this project will reduce the extended timeline for FDA approval that has been observed with previous PET radiotracers. Building on the success of our Phase I STTR project (1R41CA2612590-01), this STTR Phase II proposal by Trevarx and Penn will minimize this timeline by establishing methods for unifying radiosynthesis, maximizing product consistency and production yield, and generating a database to manage a larger supply chain for [18F]FTT. We aim to establish a new paradigm for rapid commercialization of PET radiopharmaceuticals by providing a “best practice” template by combining efforts in academic centers and commercial radiopharmaceutical supplier prior to Phase 3 to efficiently bring a novel PET radiotracer to market. Our STTR Phase II proposal establishes a roadmap to move from a single center academic trial to Phase 3 multi-center trials to efficient cGMP commercial production upon NDA approval. In this revised application, we provide more details on [18F]FTT production ( i.e., synthesis kit development and product formulation) and our strategy for the combined academic/commercial rollout of our radiotracer to prepare for the Phase 3 multi-center clinical trial recommended by the FDA in our Pre-IND meeting.

抽象的：聚（ADP-核糖）聚合酶抑制剂（PARPi）已成为针对以下疾病的重要治疗药物：扩大了批准用于治疗乳腺癌、卵巢癌、前列腺癌和其他癌症的基因突变类别。 BRCA 相关基因和肿瘤同源修复缺陷的基因组检测作为伴随 PARPi 治疗的诊断，但对 Trevarx Biomedical 反应的预测效果不完善。 Inc. (Trevarx) 的产品 [18F]Fluorthanatrace ([18F]FTT) 是 PARPi、rucaparib 的 PET 放射性标记类似物，为所有批准的 PARPi 提供区域 PARP 表达和药物参与的定量图像。因此可以作为 PARPi 伴随诊断来识别那些最有可能对 PARPi 治疗做出反应的人，并且重要的是，那些不太可能做出反应的患者在单中心临床试验中进行了成像检查，支持了这一观点。 [18F]FTT 肿瘤摄取的准确性作为区域 PARPi 药物结合的体内测量，并作为有效的与 FDA 举行的 IND 前会议表明，基于成像的 PARP-1 蛋白水平生物标志物将获得批准。要求：(1) 肿瘤样本中 [18F]FTT 摄取和 PARP-1 蛋白表达相关的 3 期组织，以及 (2) [18F]FTT 预测 PARPi 反应准确性的多中心 2 期研究 3 中心 2 期试验。 PET 组织比较研究已作为更大规模 3 期试验的试点启动，并取得了新的进展 [18F]FTT 预测准确性的中心 2 期结果强烈支持 2 期多中心试验该提案的重点是建立广泛的放射性药物供应以支持扩大批准和后续临床转化所需的多中心试验。凭借 3 年的竞争领先优势，[18F]FTT 预计将进入第 3 期示踪剂组织试验和多中心阶段 2 项预测功效试验，以支持 2025 年的 NDA。该项目中描述的步骤将减少延长的时间 FDA 批准的时间表与之前的 PET 放射性示踪剂的成功相同。我们的第一阶段 STTR 项目 (1R41CA2612590-01)，Trevarx 和 Penn 的 STTR 第二阶段提案将最大限度地减少通过建立统一放射合成、最大化产品一致性和生产的方法来实现这一时间表产量，并生成一个数据库来管理更大的 [18F]FTT 供应链。通过提供“最佳实践”模板，建立 PET 放射性药物快速商业化的范例在第三阶段之前结合学术中心和商业放射性药物供应商的努力我们的 STTR 第二阶段提案制定了行动路线图，有效地将新型 PET 放射性示踪剂推向市场。从单中心学术试验到三期多中心试验再到高效的cGMP商业化生产 NDA 批准。在此修订后的申请中，我们提供了有关 [18F]FTT 生产（即合成试剂盒）的更多详细信息。开发和产品配方）以及我们的学术/商业联合推广战略放射性示踪剂，为 FDA 在我们的 IND 前会议上推荐的 3 期多中心临床试验做准备。