Integration of Imaging and Circulating Plasma Cell-Free DNA Sequencing Using MSK-ACCESS to Monitor Treatment Response and Predict Progression in Patients With Multiple Cancers on Targeted Therapy

使用 MSK-ACCESS 整合成像和循环血浆无细胞 DNA 测序来监测治疗反应并预测多种癌症患者的靶向治疗进展

• 批准号: 10503104
• 负责人: Michael F. Berger
• 金额: $ 73.41万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503104
• 关键词: Area; Biological Assay; Biological Markers; Categories; Clinical; Clinical Trials; Collection; Complement; DNA sequencing; Data; Development; Disease; Enrollment; Failure; Foundations; Frequencies; Future; Gene Frequency; Genome; Goals; Guidelines; Healthcare; Image; Liquid substance; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Memorial Sloan-Kettering Cancer Center; Methods; Monitor; Mutation; Outcome; Patients; Pharmaceutical Preparations; Phase; Plasma; Plasma Cells; Positron-Emission Tomography; Precision therapeutics; Progression-Free Survivals; Progressive Disease; Radiology Specialty; Research; Role; Sampling; Scientist; Services; Stable Disease; Testing; Time; Treatment Side Effects; Tumor Burden; Tumor Tissue; X-Ray Computed Tomography; base; cancer therapy; cancer type; cell free DNA; co-clinical trial; cone-beam computed tomography; cytotoxic; deep sequencing; drug development; early phase clinical trial; experience; falls; genetic variant; genomic profiles; imaging modality; imaging scientist; immunomodulatory therapies; immunoregulation; improved; improved outcome; individualized medicine; insight; liquid biopsy; next generation sequencing; novel; novel therapeutics; partial response; precision medicine; prospective; response; success; targeted treatment; tool; treatment response; trend; tumor; tumor DNA

PROJECT SUMMARY The development of novel therapies is at the core of improving cancer outcomes worldwide. However, currently used metrics to capture clinical benefit of these novel therapies may not always capture treatment success or failure. The overarching goal of the proposed research is to increase precision by leveraging metrics that integrate imaging with other measures of tumor response such as changes in plasma circulating tumor DNA (ctDNA) in patients undergoing novel therapies. The proposed research builds on clinical proof-of-principle by the investigative team using next-generation sequencing (NGS) of ctDNA that decreases in variant allele frequency (VAF) of selected alterations can be observed prior to conventional radiologic response, and that increases in VAF often occur several weeks to months before radiologic progression. Building on the foundation of NGS, MSK-ACCESS, a highly sensitive deep sequencing liquid biopsy assay, was recently developed by the investigative team based on its FDA-authorized counterpart MSK-IMPACT performed on tumor tissue, which enables the identification of actionable genetic alterations that can be targeted with drugs. Additionally, the research builds upon extensive experience of the investigative team with “basket trials” evaluating the activity of precision genome-driven and immunomodulatory therapies, whereby the enrolling criterion is a putative biomarker regardless of cancer type, which has put a premium on serially collecting co-clinical trial ctDNA samples along with MSK-IMPACT testing on the tumor tissue, providing a baseline genomic profile to guide ctDNA-based disease monitoring. The diverse and extensive collection of prospectively collected ctDNA samples within these trials provides timepoints that can be compared to regulatory grade pre-treatment, on-treatment, and post-progression imaging assessments via computed tomography (CT) and/or magnetic resonance imaging (MRI), and positron emission tomography (PET). Specific Aim 1: To evaluate the correlation between early changes in ctDNA variant allele frequencies (VAF) with best response to therapy via conventional and advanced imaging assessments in early-phase targeted or immunomodulatory clinical trials. Specific Aim 2: To identify if plasma ctDNA trends can more precisely predict longitudinal clinical benefit (measured by progression-free survival) in patients who fall within the broad response category of stable disease via RECIST in early-phase clinical trials. Specific Aim 3: To identify the median time prior to which rising ctDNA levels presages eventual radiologic progression in patients who initially benefit from targeted or immunomodulatory therapy (i.e., complete/partial response or stable disease as best overall response) in early-phase clinical trials. Impact: The insights from this study will lay the groundwork for integrating advanced imaging and ctDNA-based biomarkers in the future that may be used by regulatory agencies around the globe for the purpose of assessing and approving novel precision therapies and ultimately allow the possibility for personalized precision medicine.

项目概要 新疗法的开发是改善全球癌症结果的核心。然而，目前 使用指标来捕捉这些新疗法的临床益处可能并不总是能捕捉到治疗的成功或 失败。拟议研究的总体目标是通过利用以下指标来提高精确度： 将成像与肿瘤反应的其他测量方法（例如血浆循环肿瘤 DNA 的变化）相结合 （ctDNA）接受新疗法的患者。拟议的研究建立在临床原理验证的基础上 研究团队使用 ctDNA 新一代测序 (NGS) 减少变异等位基因 可以在常规放射学反应之前观察到选定改变的频率（VAF），并且 VAF 的增加通常发生在放射学进展前几周至几个月。建立在基础之上 NGS 的 MSK-ACCESS 是一种高度灵敏的深度测序液体活检检测方法，由 NGS 最近开发 研究小组基于 FDA 授权的对应 MSK-IMPACT 对肿瘤组织进行了研究， 能够识别可用于药物靶向的可操作的基因改变。此外， 研究建立在调查团队通过“篮子试验”评估活动的丰富经验的基础上 精确的基因组驱动和免疫调节疗法，其中招募标准是假定的 无论癌症类型如何，生物标记物都非常重视连续收集临床试验 ctDNA 样本以及对肿瘤组织的 MSK-IMPACT 测试，提供基线基因组图谱来指导 基于 ctDNA 的疾病监测。前瞻性收集的 ctDNA 样本的多样化和广泛收集 这些试验中提供的时间点可以与监管级的治疗前、治疗中、 通过计算机断层扫描 (CT) 和/或磁共振成像进行进展后成像评估 (MRI) 和正电子发射断层扫描 (PET)。具体目标 1：评估早期之间的相关性 ctDNA 变异等位基因频率 (VAF) 的变化对常规和先进治疗有最佳反应 早期靶向或免疫调节临床试验中的成像评估。具体目标 2：确定是否 血浆 ctDNA 趋势可以更准确地预测纵向临床获益（通过无进展情况来衡量） 早期阶段 RECIST 属于稳定疾病广泛缓解类别的患者 临床试验。具体目标 3：确定 ctDNA 水平上升预示最终发生的中位时间 最初受益于靶向或免疫调节治疗的患者的放射学进展（即， 早期临床试验中的完全/部分缓解或疾病稳定作为最佳总体缓解）。影响： 这项研究的见解将为整合先进成像和基于 ctDNA 的生物标志物奠定基础 未来可能会被全球各地的监管机构用于评估和 批准新颖的精准疗法，并最终使个性化精准医疗成为可能。