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

乳腺癌 PARP PET 成像 AIP 支持 FDA 批准

• 批准号: 10377412
• 负责人: Sean Denis Carlin
• 金额: $ 60.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-24 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377412
• 关键词: Autoradiography; BRCA mutations; Binding; Biological Assay; Biological Markers; Breast; Cancer Center; Cancer Patient; Chemistry; Clinical Data; Clinical Trials; Data; Defect; Development; Diagnosis; Diagnostic; Elements; Formalin; Freezing; Future; Gene Mutation; Image; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Label; Lead; Licensing; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Methodology; Methods; Multicenter Trials; Ovarian; PET/CT scan; Paraffin Embedding; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase III Clinical Trials; Poly(ADP-ribose) Polymerases; Polymerase; Positron-Emission Tomography; Principal Investigator; Production; Prostate; Protocols documentation; Radiopharmaceuticals; Reference Standards; Research; Site; Standardization; Testing; Time; Tissue Embedding; Tissues; Toxic effect; Tracer; Universities; Validation; Washington; analog; base; clinical translation; commercialization; design; diagnostic accuracy; homologous recombination; imaging biomarker; improved; in vivo; industry partner; inhibitor; inhibitor therapy; malignant breast neoplasm; mutation assay; neoplastic cell; novel therapeutics; phase 3 study; phase II trial; phase III trial; predicting response; programs; prospective; targeted treatment; trial comparing; trial design; tumor; uptake

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.

摘要： 聚（ADP-核糖）聚合酶（PARP）抑制剂药物（PARPi）已成为重要的新治疗药物 靶向存在于乳腺、卵巢、前列腺和许多其他肿瘤中的基因突变的扩大类别的药物 癌的可能从PARPi中获益的患者的鉴定依赖于对同源基因缺陷的测定。 重组（HRD），如BRCA 1/2突变，但这些检测方法一直是不完善的反应预测 PARPi的。药物与肿瘤细胞中存在的PARP 1结合是有效PARPi的常见和必要因素 疗法[18F]氟噻那曲（FTT）是PARPi rucaparib的PET标记类似物， 卵巢癌和乳腺癌试验支持[18F]FTT肿瘤摄取作为局部PARP 1药物的体内测量 结合，并表明[18 F]FTT PET作为PARPi预测性成像生物标志物的潜力。[18F]FTT可以 因此，通过识别那些最有可能对乳腺癌和其他癌症产生反应的患者， PARPi疗法，同时避免那些不会对毒性，不必要的费用和浪费产生反应的人 时间 为了进一步发展，临床翻译，和商业化的[18 F]FTT，我们提出了一个学术 工业合作伙伴关系（AIP）由宾夕法尼亚大学（（Penn），主要学术合作伙伴），医学博士 安德森癌症中心（MDACC）和华盛顿大学（WU）与Trevarx生物医学公司（Trevarx）。 Trevarx是一家拥有[18F]FTT独家许可证的放射性制药公司，正在开发[18F]FTT作为一种 成像生物标志物以指导PARPi治疗，第一适应症为乳腺癌。根据与 FDA和顾问，[18 F]FTT批准将需要对[18 F]FTT PET/CT的准确性进行III期研究， 诊断PARP 1表达的癌症。本AIP提案的目标侧重于必要的关键组件， [18F]FTT FDA批准的III期试验：（1）Trevarx持有的IND，标准化示踪剂生产 方法学和产品质量标准;（2）PARP 1免疫组织化学（IHC）测定的验证 福尔马林固定石蜡包埋（FFPE）组织中的表达，作为[18 F]FTT PET的参考标准 诊断准确性;（3）2期多中心试验，以在多中心环境中测试和验证方法 并为设计关键的3期试验提供初步数据。这些目标的完成将使一个阶段 3项试验支持[18 F]FTT FDA批准、[18 F]FTT的商业供应以及学术界正在进行的研究 合作伙伴记录[18F]FTT PET/CT用于指导PARPi治疗的价值，包括前瞻性多项 中心生物标志物为重点的研究。