Developing a kit-based research use only (RUO) translocation assay for deployment as a lab developed test (LDT) toward changing outcomes for patients with driver-negative tumors

开发基于试剂盒的仅供研究使用 (RUO) 的易位测定，作为实验室开发的测试 (LDT) 部署，以改变驱动阴性肿瘤患者的结果

• 批准号: 10678597
• 负责人: Siddarth Selvaraj
• 金额: $ 206.97万
• 依托单位: ARIMA GENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678597
• 关键词: 3-Dimensional; Acceleration; Adoption; Advanced Malignant Neoplasm; Automobile Driving; Award; Awareness; Biological Assay; Biopsy; Cancer Diagnostics; Cancer Patient; Cell Nucleus; Cessation of life; Classification; Clinical; Clinical Data; Clinical Research; Creativeness; DNA; Data; Detection; Diagnosis; Ecosystem; Event; Failure; Future; Gene Fusion; Genetic; Genome; Genomics; Goals; Guidelines; Hand; Healthcare Systems; Informatics; Label; Laboratories; Large Intestine Carcinoma; Letters; Light; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Marketing; Measurement; Measures; Methods; Mission; Mutation; Neighborhoods; Non-Small-Cell Lung Carcinoma; Oncologist; Outcome; Pathologist; Pathology; Patient Care; Patient-Focused Outcomes; Patients; Performance; Phase; Press Releases; Prognosis; Provider; Publications; RNA; Recovery; Reporting; Reproducibility; Research; Sampling; Series; Severities; Shapes; Specificity; Technology; Teenagers; Testing; Tumor stage; Uterine Corpus Sarcoma; Validation; bridge program; cancer care; clinical care; clinically actionable; commercialization; genetic profiling; girls; improved; individualized medicine; insight; lens; manufacture; meetings; pembrolizumab; personalized medicine; precision medicine; preservation; product development; programmed cell death ligand 1; programs; prospective; success; targeted treatment; technology platform; therapy resistant; tumor

Developing a kit-based research use only (RUO) translocation assay for deployment as a lab developed test (LDT) toward changing outcomes for patients with driver-negative tumors (RFA sub-section: Technology platform for Cancer Diagnostics) SUMMARY Nearly 1M patients are diagnosed with advanced stage cancer per year. One case dear to Arima is a teenage girl who was diagnosed with advanced brain cancer. Her tumor had been tested twice using state-of-the-art NGS-based lab developed tests (LDTs), but no actionable genetic driver could be found, classifying her tumor as “driver-negative”, precluding access to targeted therapies and greatly reducing her likelihood of survival. However, thanks to the parental phase-2 award, Arima had just developed an NGS technology platform – the T-Seq kit – to detect tumor driving translocations and gene fusions from tumor biopsies. Lo and behold, when T-Seq analyzed this patient’s tumor, it revealed a translocation implicating PD-L1, triggering a series of events leading to treatment with pembrolizumab and 9 months later no signs of tumor, all thanks to T-Seq. This proposal strives to scale this clinical origin story to make a widespread impact in the 50% of patients with advanced cancers and no detectable genetic drivers (~488,000 patients per year in US). However, to make this widespread impact, T-Seq technology must be made available to oncologist and pathologist in the form of an LDT. The overarching goal of this proposal is to execute all necessary steps to develop and validate T-Seq kits so that they can be supplied to CLIA labs who will validate and deploy T-Seq as an LDT to inform clinical care. Thanks to our parental phase-2, execution towards this goal has already begun. From a tech perspective T- Seq kits are more sensitive than existing tech because they profile translocations through the lens of a spatial 3D genome, rather than a linear genome, enabling detection of tumor driving translocations like PD-L1 that are otherwise missed. T-Seq technology has also been productized, meeting all the key product products for deployment as an LDT, culminating in the launch of a kitted end-to-end T-Seq workflow. Lastly, T-Seq kit performance is concordant with existing tech, yet it detects tumor-driving translocations in 54% of driver- negative tumors, including 4 patients where the course of clinical care has been altered thanks to T-Seq. With a product in hand and foundational clinical data, the proposed aims accomplish the remaining steps towards our goal of becoming a tech provider to CLIA labs. Specifically, this proposal first aims to establish competitive analytical performance metrics for T-Seq. Then it aims to demonstrate clinical validity and utility of T-Seq across mainline tumor types, and in clinical contexts of severe unmet need. Lastly, the proposal aims to validate and deploy T-Seq kits in partnering academic and commercial CLIA laboratories. The success of each proposed aims is measured using multiple quantitative metrics relevant to that aim, informed by CLIA assay validation guidelines and key metrics defined by stakeholders in the LDT ecosystem. By the conclusion of the phase-2b program, the ultimate goal of becoming a technology provider to CLIA labs will be accomplished, whereby T-Seq kits will be deployed as LDTs in initial academic and commercial CLIA labs, and clinical data, publications, and awareness of T-Seq will be established to accelerate future adoption of T-Seq as an LDT.

开发基于试剂盒的仅供研究使用 (RUO) 的易位测定，以作为实验室开发进行部署 测试（LDT）以改变驱动阴性肿瘤患者的结果（RFA 小节： 癌症诊断技术平台） 概括 每年有近 100 万患者被诊断患有晚期癌症。 Arima 所关心的一个案例是一名青少年 被诊断患有晚期脑癌的女孩。她的肿瘤已经使用最先进的技术进行了两次测试 基于 NGS 的实验室开发了测试 (LDT)，但无法找到可操作的基因驱动因素，无法对她的肿瘤进行分类 被诊断为“驾驶员阴性”，无法获得靶向治疗并大大降低了她的生存可能性。 然而，得益于母公司二期奖项，华冠刚刚开发了一个NGS技术平台—— T-Seq 试剂盒——从肿瘤活检中检测肿瘤驱动易位和基因融合。你瞧，当 T-Seq 分析了该患者的肿瘤，发现涉及 PD-L1 的易位，引发了一系列事件 导致使用 pembrolizumab 治疗，9 个月后没有出现肿瘤迹象，这一切都归功于 T-Seq。这 该提案力求扩大这一临床起源故事，对 50% 的患者产生广泛影响 晚期癌症且没有可检测到的遗传驱动因素（美国每年约有 488,000 名患者）。然而，为了使这 由于影响广泛，T-Seq 技术必须以 LDT。该提案的总体目标是执行所有必要的步骤来开发和验证 T-Seq 试剂盒 以便将它们提供给 CLIA 实验室，后者将验证 T-Seq 并将其部署为 LDT，为临床护理提供信息。 感谢我们的父母第二阶段，实现这一目标的执行已经开始。从技术角度来看T- 测序套件比现有技术更灵敏，因为它们通过空间透镜来分析易位 3D 基因组，而不是线性基因组，能够检测肿瘤驱动易位，如 PD-L1 否则错过了。 T-Seq技术也已经产品化，满足了所有关键产品 作为 LDT 进行部署，最终推出配套的端到端 T-Seq 工作流程。最后，T-Seq 试剂盒 性能与现有技术一致，但它检测到 54% 的驱动基因中的肿瘤驱动易位 阴性肿瘤，包括 4 名患者，由于 T-Seq，他们的临床护理过程发生了改变。 有了现有的产品和基础临床数据，拟议的目标就可以完成剩余的步骤 实现成为 CLIA 实验室技术提供商的目标。具体来说，该提案首先旨在建立 T-Seq 的竞争性分析性能指标。然后旨在证明临床有效性和实用性 跨主线肿瘤类型以及严重未满足需求的临床环境中的 T-Seq。最后，该提案旨在 在学术和商业 CLIA 实验室合作中验证和部署 T-Seq 试剂盒。每个人的成功 通过 CLIA 检测，使用与该目标相关的多个定量指标来衡量拟议的目标 LDT 生态系统中的利益相关者定义的验证指南和关键指标。通过结论 Phase-2b计划，成为CLIA实验室技术提供商的最终目标将实现， T-Seq 试剂盒将作为 LDT 部署在最初的学术和商业 CLIA 实验室以及临床数据中， 将建立 T-Seq 的出版物和意识，以加速未来采用 T-Seq 作为 LDT。