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

I-SPY 2试验通过其在乳腺癌新辅助治疗中的应用， 设计为II期、多中心平台试验。自2010年推出以来，已有24种新的疗法或组合， 测试，7个被发现显着改善病理完全反应（pCR），导致几个明确的阶段， 第三次审判。然而，随着这一成功，人们意识到并非每个病人都受益， 标准治疗方案的代价是增加了毒性。2015年，I-SPY P01进一步推动了 解决这些问题的工具，包括更好地评估个体患者对治疗和后续治疗反应的工具 无事件生存结局，这使得反应差的患者能够升级，而反应异常的患者能够降级。 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 铂和其他药物能够避免蒽环类药物的毒性，这是治疗的关键初始步骤 个性化和精准医疗。这些创新导致了在整个过程中的共同决策， 新辅助治疗，需要扩大参与试验的研究中心数量。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工作 在I-SPY 2试验中，我们的团队在设计下一代试验I-SPY 2时发挥了重要作用。2.我们 现在假设，通过进一步完善I-SPY 2.2试验中的升级和降级过程，包括 将循环肿瘤DNA（ctDNA）和我们新的反应预测亚型模式整合到关键决策中 在整个试验人群中，我们可以提高达到pCR的患者比例 通过更好地匹配患者的药物，最大限度地提高个人的pCR机会， 同时降低治疗的毒性并改善患者的健康。项目1将在 在试验过程中，实时、基于生物标志物的决策的周期性改进过程， 目标是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局。在 项目1，我们将进一步利用项目2-4的工作，对顺序随机化进行改进 （递增策略）为疗效差的患者提供同类最佳的补救治疗，并降低剂量，以尽量减少不必要的 特殊反应者的治疗。我们将开发新的措施来比较测试的代理人，如在RCB的变化 分布（作为试验组水平的近似结果）以及疗效和毒性（包括患者- 报告结果（PRO）。PRO和结果返回流程也将用于评价对患者的影响 感知、共同决策和不良心理后果的预测因素。最后，我们将进一步加强 I-SPY 2.2 II期基础设施，为证明成功的疗法和/或序列添加调节途径 在新辅助治疗中改善结果和/或降低毒性。

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.