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

I-SPY2 试验通过其新辅助疗法加速了乳腺癌新疗法的开发 设计为 II 期、多中心平台试验。自 2010 年推出以来，已有 24 种新疗法或联合疗法 经过测试，发现 7 种可显着改善病理完全缓解 (pCR)，从而进入几个确定阶段 三、试验。然而，随着这一成功，我们意识到并非每个患者都能受益，并且连续添加药物 标准治疗方案的代价是毒性增加。 2015年，I-SPY P01引领了进一步发展 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 无事件生存结果，这使得反应不佳的人能够升级，而特殊的人则能够降级 响应者。这导致一些患者接受额外的治疗，例如免疫检查点抑制剂或 铂类和其他药物能够放弃蒽环类药物等药物的毒性，这是治疗的关键初始步骤 个体化和精准医疗。这些创新导致了整个过程中的共同决策 新辅助治疗需要扩大参与试验的地点数量。项目 1 是 有助于协调其他项目在开发这些工具、实施和验证这些工具方面的努力 在 I-SPY2 试验中，并激励 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 将循环肿瘤 DNA (ctDNA) 和我们的新型反应预测亚型模式整合到关键决策中 流程和时间点，我们可以提高整个试验人群中达到 pCR 的患者比例 并通过更好地将患者与药物相匹配来最大限度地提高个人获得 pCR 的机会，同时减少复发 同时减少治疗的毒性并改善患者的健康。项目 1 将在 试验过程中基于生物标志物的实时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果。在 项目1，我们将进一步利用项目2-4的工作对序贯随机化进行细化 （升级策略）为反应不佳者提供一流的救援疗法，并降级以最大程度地减少不必要的影响 特殊反应者的治疗。我们将制定新的措施来比较测试的药物，例如 RCB 的变化 分布（作为试验组水平的近似结果）以及功效和毒性的综合测量（包括患者- 报告结果（PRO））。 PRO 和结果返回流程也将用于评估对患者的影响 感知、共同决策以及不良心理结果的预测因素。最后，我们将进一步构建 I-SPY2.2 II 期基础设施为证明成功的治疗和/或序列添加监管途径 改善新辅助治疗的结果和/或减少毒性。

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.