The I SPY 2.2 TRIAL: Evolving to Imaging and Molecular Biomarker Response Directed Adaptive Sequential Treatment to Optimize Breast Cancer Outcomes

I-SPY计划项目在高级临床试验设计的背景下推进个性化治疗的目标 这有助于不断改进成果。在这个节目中，我们关注的是处于第二阶段和第三阶段的女性 高风险的早期乳腺癌，他们快速发展和死亡的风险最高。I-SPY2.2计划项目 使我们能够生成以患者为中心的临床药物开发方法，以优化个人、生物标记物- 通过根据治疗反应升级或降低治疗的针对性治疗，在试验的背景下这样做 这有效地评估了新的潜在一线药物和治疗方案。在以下方面发展的经验和见解 该计划项目将广泛适用于乳腺癌以外的其他癌症和临床试验设计。 I-SPY2.2方案项目的继续将为最终 将提高完全应答率(PCR)并防止转移。拟议的四个项目和三个共享资源核心 将允许我们创建策略来组合来自肿瘤的多个生物标记物分析物和在 循环以建立新辅助治疗环境中缺乏反应和不良结局的越来越好的预测模型 并进一步确定残留病中的“可用药”靶点，以减轻耐药性。I-SPY计划和该计划 项目实际上已经为乳腺癌治疗结果建立了一个持续改进的系统，使我们能够 推动乳腺癌精准医学的进步，重要的是，使用高度以患者为中心的框架。迭代 这一过程将导致更多和更好的靶向治疗，通过利用生物洞察力，改善反应- 预测性生物标志物，以及综合疗效和对生活质量的影响。这些元素的组合 将拯救生命，减少发病率，并为改进个性化和转化为临床实践奠定基础。 在过去5年的i-SPY2.2计划项目中，我们达到了所有规定的目标，创建和实施(6月 2022)一种新颖、创新的试验设计，既测试新型制剂，又在治疗过程中进行个性化护理。在……里面 在接下来的五年里，我们将反复改进这些进程，通过及早降低 在成功情况下的治疗，以及在最小反应情况下的早期升级治疗，基于我们的 建立和改进定量乳腺MRI作为反应评估的生物标记物的创新。我们将使用 整合的分子和免疫反应-在头五年开发的预测亚型，用于分配治疗 靶向药物最初没有标准的化疗药物，但如果反应不充分，则按顺序进行。我们会 根据我们开发的改进的、反应预测的亚型对治疗进行随机化，以测试他们准确地 分配治疗方案。我们将使用顺序多重分配方法(SMART)来确定 并使用该框架整合无缝的2/3期试验，以加快获得最有效的过程， 在尽可能短的时间内对妇女采取毒性最小的治疗策略。拟议方案项目的基础设施 致力于项目目标的紧密整合、经验丰富的多学科团队将使我们能够 实现我们的目标，并影响患有高危乳腺癌的女性的生活。

The I-SPY Program Project advances the goals of personalized treatment in the setting of an advanced clinical trial design that facilitates continuous improvement in outcomes. In this program, we focus on women with stage 2 and 3 molecularly high-risk, early breast cancer who have the highest risk for rapid progression and death. The I-SPY2.2 program project allows us to generate a patient-centric approach to clinical drug development that optimizes individual, biomarker- targeted treatments by escalation or de-escalation of therapy based on treatment response, doing so in the context of a trial that efficiently evaluates novel potential first-line agents and treatment regimens. The lessons and insights developed in this program project will be broadly applicable beyond breast cancer to other cancers and to clinical trial design. The continuation of the I-SPY2.2 program project will provide the resources for the discovery research that ultimately will increase complete response (pCR) and prevent metastases. The proposed four projects and three shared resource cores will allow us to create strategies for combining multiple biomarker analytes from the tumor and derivatives assessed in circulation to build better and better predictive models of lack of response and poor outcome in the neoadjuvant setting and further identify ‘druggable’ targets in residual disease to alleviate resistance. The I-SPY program and the Program Project have, in effect, established a continuous improvement system for breast cancer treatment outcomes, enabling us to drive progress in precision medicine for breast cancer, importantly, using a highly patient-centric framework. The iterative process will lead to more and better targeting of therapies by leveraging biologic insights, refinement of response- predictive biomarkers, and integration of both efficacy and impact on quality of life. The combination of these elements will save lives, reduce morbidity and set the stage for improved personalization and translation to clinical practice. In the past 5 years of the I-SPY2.2 program project, we have met all of our stated aims, creating and implementing (June 2022) a novel, innovative trial design to both test novel agents and individualize care over the course of the treatment. In the subsequent five years, we will iteratively refine the processes to optimize outcomes through early de-escalation of treatment in the setting of success, and early escalation of treatment in the setting of minimal response, based on our innovations in establishing and refining quantitative breast MRI as a biomarker of response assessment. We will use integrated molecular and immune response-predictive subtypes developed in the first five years to assign treatments for targeted agents initially without standard chemotherapeutics, but then in sequence if response is not sufficient. We will randomize treatments based on the improved, response-predicted subtypes we developed to test their ability to precisely assign treatments. We will use a sequential multiple assignment approach (SMART) to identify optimal sequences of therapy and use the framework to integrate a seamless phase 2/3 trial that will speed the process of getting the most effective, least toxic treatment strategies to women in the shortest possible time. The infrastructure of the proposed program project and the tightly integrated, experienced multidisciplinary team that is dedicated to the goals of the program will enable us to accomplish our goals and impact the lives of women with high-risk breast cancer.