Project 1: Imaging, pathology, and molecular biomarkers to Optimize Treatment Switching within a SMART adaptive Framework

项目 1：利用影像学、病理学和分子生物标志物在 SMART 自适应框架内优化治疗切换

• 批准号: 10628609
• 负责人: ANGELA DEMICHELE
• 金额: $ 34.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628609
• 关键词: Accelerated Phase; Acceleration; Address; Adverse event; Anthracycline; Anxiety; Biological Markers; Breast Cancer therapy; Cancer Burden; Caring; Cessation of life; Clinical; Clinical Drug Development; Clinical Treatment; Clinical Trials; Clinical Trials Design; Conduct Clinical Trials; Conflict (Psychology); Core Biopsy; Decision Making; Development; Dimensions; Disease; Disease Outcome; Disease-Free Survival; Distant; Distant Metastasis; Distress; ERBB2 gene; Early treatment; Eligibility Determination; Ensure; Evaluation; Functional Magnetic Resonance Imaging; Goals; Image; Immune checkpoint inhibitor; In complete remission; Individual; Infrastructure; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Medical Imaging; Methods; Monitor; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Pathology Report; Patient Outcomes Assessments; Patients; Perception; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physicians; Platinum; Population; Prediction of Response to Therapy; Preparation; Process; Randomized; Recommendation; Recurrence; Regimen; Regrets; Regulatory Pathway; Relapse; Reporting; Residual Cancers; Self Efficacy; Sequential Treatment; Series; Site; Surrogate Markers; Testing; Time; Toxic effect; Treatment Protocols; Treatment outcome; Treatment-related toxicity; Tumor Volume; Woman; Work; arm; breast imaging; cancer type; clinical decision-making; confirmatory trial; cost; design; drug development; exceptional responders; high risk; imaging biomarker; improved; improved outcome; individual patient; individual variation; individualized medicine; innovation; malignant breast neoplasm; molecular marker; next generation; novel; novel therapeutics; patient population; personalized medicine; phase 2 testing; phase III trial; precision medicine; predicting response; programs; prospective; psychological outcomes; randomized trial; response; response biomarker; shared decision making; standard of care; success; survival outcome; targeted biomarker; targeted treatment; therapy design; tool; tool development; treatment and outcome; treatment optimization; treatment response; trial design; triple-negative invasive breast carcinoma; tumor; tumor DNA; tumor progression

The I-SPY2 Trial accelerated development of novel therapies for breast cancer in the neoadjuvant setting through its design as a phase II, multicenter platform trial. Since launching in 2010, 24 new therapies or combinations have been tested, and 7 were found to significantly improve pathologic complete response (pCR), leading to several definitive phase III trials. However, with this success came the realization that not every patient benefited, and the serial addition of drugs to the standard regimen came at a cost in terms of increased toxicity. In 2015, the I-SPY P01 led to further development of tools that address these issues, including tools to better evaluate individual patient responses to therapy and subsequent event-free survival outcomes, that have enabled escalation for poor responders and de-escalation for exceptional responders. This has led to some patients receiving additional therapies such as immune checkpoint inhibitors or platinums and others being able to forego the toxicity of agents such as anthracyclines, key initial steps toward treatment individualization and precision medicine. These innovations have led to shared decision-making over the course of neoadjuvant therapy and necessitated the expansion of the number of sites to participate in the trial. Project 1 was instrumental in coordinating the efforts of the other projects in developing these tools, implementing and validating them within the I-SPY2 trial as well as galvanizing the I-SPY Trial team in designing the next generation trial, I-SPY2.2. We now hypothesize that by further refining the process of escalation and de-escalation in the I-SPY2.2 Trial, including the integration of circulating tumor DNA (ctDNA) and our novel Response Predictive Subtype schema into key decision processes and timepoints, we can improve the proportion of patients who achieve pCR across the entire trial population and reduce recurrence, through better matching patients to drugs that maximize an individual’s chance for pCR while concurrently reducing toxicity of treatment and improving patient well-being. Project 1 will test this hypothesis in the process of cyclical improvements in the real-time, biomarker-based decision making along the course of the trial, with the goal of further optimizing outcomes for individual patients in the context of drug development for early breast cancer. In Project 1, we will further leverage the work of Projects 2-4 to implement refinements to the sequential randomization (escalation strategy) to best-in-class rescue therapies for poor responders and de-escalation to minimize unnecessary therapy in exceptional responders. We will develop novel measures to compare tested agents, such as changes in the RCB distribution (as trial arm level proximate outcome) and composite measures of efficacy and toxicity (including patient- reported outcomes (PRO)). PRO and a return of results process will also be used to evaluate impacts on patient perception, shared decision-making, and predictors of adverse psychological outcomes. Finally, we will further build onto the I-SPY2.2 phase II infrastructure to add a regulatory pathway for therapies and/or sequences that demonstrate success in improving outcomes and/or reducing toxicity in the neoadjuvant setting.

I-SPY2试验加速了乳腺癌新疗法的开发，通过其 设计为第二阶段、多中心平台试验。自2010年推出以来，已经推出了24种新的疗法或组合 测试，其中7个被发现显著改善了病理完全应答(PCR)，导致了几个最终阶段 III试验。然而，随着这一成功而来的是意识到并不是每个患者都受益，以及连续增加药物 标准方案的代价是毒性增加。2015年，i-spy P01导致了进一步的发展 解决这些问题的工具，包括更好地评估个别患者对治疗和后续治疗的反应的工具 无事件生存结果，这使得响应能力差的人员能够上报，而特殊情况下的情况会降级 响应者。这导致一些患者接受额外的治疗，如免疫检查点抑制剂或 Platinum和其他能够放弃蒽环类药物毒性的药物，这是治疗的关键初始步骤 个性化、精准化医疗。这些创新在整个过程中实现了共享决策 新辅助治疗和扩大参与试验的地点数目是必要的。项目1是 有助于协调其他项目在开发、实施和验证这些工具方面的努力 在i-SPY2试验中，以及激励i-spy试验团队设计下一代试验，i-SPY2.2。我们 现在假设通过进一步完善i-SPY2.2试验中的升级和降级过程，包括 循环肿瘤DNA(CtDNA)和我们新的反应预测亚型模式在关键决策中的集成 流程和时间点，我们可以提高整个试验人群中实现聚合酶链式反应的患者比例 并通过更好地将患者与药物匹配来最大化个体获得聚合酶链式反应的机会来减少复发 在减少治疗毒性的同时，改善患者的福祉。项目1将在 在试验过程中对基于生物标志物的实时决策进行周期性改进的过程，以及 在早期乳腺癌药物开发的背景下，进一步优化个体患者的结果。在……里面 项目1，我们将进一步利用项目2-4的工作来实施对顺序随机化的细化 (上报战略)为反应不佳的人员提供一流的救援治疗，并降低上报，以最大限度地减少不必要的情况 对特殊应答者的治疗。我们将开发新的方法来比较被测试的试剂，例如RCB的变化 分布(作为试验手臂水平的近期结果)和疗效和毒性的综合测量(包括患者- 报告结果(PRO))。还将使用PRO和返回结果流程来评估对患者的影响 感知、共同决策和不利心理结果的预测因素。最后，我们将进一步加强 I-SPY2.2阶段II基础设施，为证明成功的治疗和/或序列增加调控途径 在新佐剂环境下改善结果和/或减少毒性。