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.

开发一种基于试剂盒的仅供研究使用（RUO）的易位检测试剂盒，用于实验室开发 试验（LDT）改变驱动因子阴性肿瘤患者的结局（RFA子章节： 癌症诊断技术平台） 总结 每年有近100万患者被诊断为晚期癌症。有马最关心的一个案例是一个十几岁的孩子， 被诊断出患有晚期脑癌的女孩她的肿瘤已经用最先进的 基于NGS的实验室开发了测试（LDT），但没有找到可操作的遗传驱动因素，对她的肿瘤进行分类 “驱动因素阴性”，无法获得靶向治疗，大大降低了她生存的可能性。 然而，由于父母阶段2奖，Arima刚刚开发了一个NGS技术平台- T-Seq试剂盒-用于检测肿瘤活检中的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，它揭示了涉及PD-L1的易位，引发了一系列事件 导致用pembrolizumab治疗，9个月后没有肿瘤迹象，这一切都归功于T-Seq。这 该提案致力于扩大这一临床起源故事，以在50%的患者中产生广泛影响， 晚期癌症和不可检测的遗传驱动因素（美国每年约488，000例患者）。然而，为了使这 T-Seq技术的广泛影响，必须提供给肿瘤学家和病理学家的形式， LDT。本提案的总体目标是执行所有必要步骤以开发和验证T-Seq试剂盒 这样它们就可以被提供给CLIA实验室，CLIA实验室将验证和部署T-Seq作为LDT，以告知临床护理。 由于我们的父母阶段2，实现这一目标的执行已经开始。从技术角度来看，T- 测序试剂盒比现有技术更敏感，因为它们通过空间的透镜来分析易位。 3D基因组，而不是线性基因组，能够检测肿瘤驱动的易位，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的需求。 作为LDT部署，最终推出了配套的端到端T-Seq工作流程。最后，T-Seq Kit 性能与现有技术一致，但它在54%的驱动程序中检测到肿瘤驱动易位， 阴性肿瘤，包括4名患者，由于T-Seq，临床护理过程已经改变。 有了产品和基础临床数据，提出的目标完成了剩余的步骤 我们的目标是成为CLIA实验室的技术供应商。具体而言，该提案首先旨在建立 具有竞争力的T-Seq分析性能指标。然后，它旨在证明临床有效性和实用性， T-Seq跨主线肿瘤类型，并在严重未满足需求的临床背景下。最后，该提案旨在 在合作的学术和商业CLIA实验室中验证和部署T-Seq试剂盒。每个人的成功 使用与该目标相关的多个定量指标来衡量拟议目标，这些指标由CLIA分析提供信息 LDT生态系统中利益相关者定义的验证指南和关键指标。在结束时， 2b阶段计划，最终目标是成为CLIA实验室的技术提供商， 由此T-Seq试剂盒将作为LDT部署在最初的学术和商业CLIA实验室中，并且临床数据， 将建立T-Seq的出版物和意识，以加速T-Seq作为LDT的未来采用。