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

项目1总结 术前病理完全应答(PCR)的侵袭性乳腺癌患者 (“新辅助”)治疗有很好的结果，尽管表现为II或III期疾病。相比之下， 接受化疗后有大量残留癌症负担(“RCB 2/3”)的妇女表现不佳。 结果，3-5年无事件生存率低于60%。大量研究和FDA的荟萃分析 证实了聚合酶链式反应作为长期生存替代物的强大预后作用。的首要目标是 项目1是利用PCR或RCB0和RCB 2/3替代物，以允许成功的i-SPY2试验进化和 测试一种新的治疗模式，使患者有更多机会达到聚合酶链式反应。《i-spy 2》 Trial已经是一个创新的、适应性强的临床试验框架，旨在加速新药开发 与治疗反应的生物标记物有关。到目前为止，超过1000名患者(每年250名)被随机分配到 12个调查治疗机构中的一个，其中5个已成功从试验中毕业。但我们有 观察到，许多妇女仍然无法达到聚合酶链式反应，而其他人对治疗的早期反应良好，以及 可能会避免额外的毒性。我们假设，通过利用基于MRI的工具来评估残留物 癌症负担(称为综合RCB，或IRCB)在新辅助治疗过程中，我们将 能够有效地将治疗转向那些反应异常或反应差的患者，而不是前者(在 IRCB预测早期PCR的人)通过允许他们更早地接受手术来进行额外的毒性治疗，而 为后者(其中iRCB预测RCB 2/3)提供基于替代的新颖的“个性化”疗法 根据他们自己的肿瘤生物学，实际上提供了实现聚合酶链式反应的“第二次机会”。为了优化响应，我们 将利用对i-SPY2出现的治疗耐药机制和标记的洞察 试验，我们选择了序贯多分配随机试验(SMART)模型，该模型允许我们 将这些创新纳入i-spy框架，最终实现对治疗的“连续”修改 对于继续表现出反应不佳的女性。项目1将利用以下方面生成的知识和工具 所有项目和核心：改进iRCB，将其作为改变治疗方向的“触发器”(项目2)； 潜在后续制剂/组合文库和基于肿瘤存在的应答概率 已知和新确定的生物标记物(项目3、4)；以及指定替代物的临床决策工具 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 2到i-spy 2+。我们的管理核心将根据我们与FDA的讨论来监督监管要求。我们的 生物信息学核心公司在设计智能和适应性试验方面拥有领先的专业知识。这部小说和 创新的方法将评估路径和个体化治疗策略，这对实现 精准医学的潜力。

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.