Project 01 - Sequential Multiple Assignment Randomization using imaging and molecular biomarkers in I-SPY 2 non-responders

项目1概要 术前达到病理完全缓解（pCR）的侵袭性乳腺癌女性 尽管表现为II期或III期疾病，但新辅助疗法（“新辅助”）具有优异的结果。与此相反， 暴露于化疗后具有大量残余癌症负荷（“RCB 2/3”）的妇女具有较差的 3-5年无事件生存率低于60%。大量研究和FDA荟萃分析 证实了pCR作为长期生存替代物的强大预后作用。的首要目标 项目1是利用pCR或RCB 0和RCB 2/3替代物，使成功的I-SPY 2试验得以发展， 测试一种新的治疗模式，使患者有更多机会达到pCR。间谍2 TRIAL已经是一个创新的，适应性的临床试验框架，旨在加速新药开发 与治疗反应的生物标志物有关。迄今为止，超过1000名患者（每年250名）被随机分配至 12个研究治疗组之一，其中5个已成功从试验中毕业。但我们有 观察到许多女性仍然未能达到pCR，而另一些女性对治疗的早期反应非常好，并且 可能会避免额外的毒性。我们假设，通过利用基于MRI的工具来评估残留的 癌症负担（称为“综合RCB，或iRCB”），我们将 能够有效地重新定向治疗那些有特殊或不良反应的人， iRCB预测早期pCR的患者）通过允许他们更早地进行手术来进行额外的毒性治疗，而 为后者（其中iRCB预测RCB 2/3）提供替代的新型“个性化”治疗， 根据他们自己的肿瘤生物学，实际上提供了实现pCR的“第二次机会”。为了优化响应，我们 将利用对I-SPY 2中出现的治疗抗性的机制和标志物的见解 TRIAL，我们选择了序贯多分配随机试验（SMART）模型， 将这些创新纳入I-SPY框架，最终实现“系列”治疗修改 对于那些反应不佳的女性来说。项目1将利用各部门产生的知识和工具， 所有项目和核心：完善iRCB，作为治疗方向调整的“触发器”（项目2）; 潜在后续药物/组合库和基于肿瘤存在的缓解概率 已知和新发现的生物标志物（项目3，4）;以及临床决策工具，用于分配替代品 基于存在多个生物标志物的反应的治疗。最终的结果将是I-SPY的演变 我们的管理核心将根据我们与FDA的讨论监督监管要求。我们 Bioinformatics Core在SMART和适应性试验设计方面拥有领先的专业知识。这本小说和 创新的方法将评估途径和个性化的治疗策略，这对实现 精准医疗的潜力

PROJECT 1 SUMMARY Women with aggressive breast cancer who achieve a pathologic complete response (pCR) to preoperative (“neoadjuvant”) therapy have excellent outcomes, despite presentation with stage II or III disease. In contrast, women with substantial residual cancer burden (“RCB 2/3”) after exposure to chemotherapy have poor outcomes, with event free survival below 60% at 3-5 years. Numerous studies and an FDA meta-analysis confirm the strong prognostic effect of pCR as a surrogate for long-term survival. The overarching goal of Project 1 is to exploit the pCR or RCB0 and RCB 2/3 surrogate to allow the successful I-SPY2 trial to evolve and test a new treatment paradigm where there are more opportunities for patients to reach a pCR. The I- SPY 2 TRIAL is already an innovative, adaptive clinical trial framework designed to accelerate new drug development tied to biomarkers of treatment response. To date, over 1000 patients (250 per year) have been randomized to one of 12 investigational treatment arms, 5 of which have successfully graduated from the trial. But we have observed that many women still fail to reach pCR, while others have excellent early response to therapy, and likely could be spared additional toxicity. We hypothesize that by utilizing an MRI-based tool to assess residual cancer burden (called the “Integrated RCB, or iRCB) midway through the course of neoadjuvant therapy, we will be able to effectively redirect treatment in those with either exceptional or poor response sparing the former (in whom iRCB predicts early pCR) additional toxic therapy by allowing them to go to surgery sooner, while providing the latter (in whom iRCB predicts RCB 2/3) with alternative novel, “personalized” therapies based upon their own tumor biology, in effect offering a `second chance' at achieving pCR. To optimize response, we will leverage insights into the mechanisms and markers of treatment resistance emerging from the I-SPY2 TRIAL, We have selected a Sequential Multiple Assignment Randomized Trial (SMART) model that permits us to incorporate these innovations within the I-SPY framework, ultimately enabling `serial' treatment modifications for women who continue to exhibit poor response. Project 1 will leverage knowledge and tools generated across all projects and cores: refinement of iRCB as the `trigger' for treatment re-direction (Project 2); an enhanced library of potential subsequent agents/combinations and probability of response based on the presence of tumor biomarkers, both known and newly identified (Projects 3, 4); and a clinical decision tool to assign substitute therapy based on the presence of multiple biomarkers of response. The end result will be the evolution of I-SPY 2 into I-SPY 2+.Our Admin core will oversee regulatory requirements as per our discussions with the FDA. Our Bioinformatics Core has leading expertise on the design of SMART and adaptive trials. This novel and innovative approach will evaluate both pathway and individualized treatment strategies critical to realizing the potential of precision medicine.