I-SPY2 +: Evolving the I-SPY 2 TRIAL to include MRI-directed, adaptive sequential treatment to optimize breast cancer outcomes

I-SPY2：改进 I-SPY 2 试验，纳入 MRI 引导的适应性序贯治疗，以优化乳腺癌结果

• 批准号: 10013133
• 负责人: LAURA J ESSERMAN
• 金额: $ 184.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013133
• 关键词: Accelerated Phase; Address; Assessment tool; Bioinformatics; Biological; Biological Markers; Biology; Biopsy; Breast; Breast Cancer Risk Factor; Breast Cancer Treatment; Cancer Burden; Characteristics; Clinical; Clinical Trials; Data; Data Set; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease-Free Survival; Drug Approval; Drug Combinations; Drug Targeting; Early identification; Evolution; Foundations; Generations; Goals; High Risk Woman; Image; Immune; Immunologics; In complete remission; Knowledge; Learning; Magnetic Resonance Imaging; Mechanics; Modeling; Modernization; Modification; Molecular; Molecular Evolution; Monitor; Neoadjuvant Therapy; New Agents; Operative Surgical Procedures; Outcome; Paclitaxel; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Positron-Emission Tomography; Prior Therapy; Process; Recurrence; Regimen; Research; Residual Cancers; Residual Tumors; Resistance; Resources; Risk; Role; Science; Selection for Treatments; Sequential Multiple Assignment Randomized Trial; Sequential Treatment; Surrogate Endpoint; Systemic Therapy; Technology; Testing; Toxic effect; Tumor Biology; Tumor Burden; Tumor Subtype; Validation; Woman; Work; base; breast cancer survival; chemotherapeutic agent; chemotherapy; clinical practice; design; experience; high risk; imaging biomarker; imaging modality; improved; improved outcome; individualized medicine; innovation; malignant breast neoplasm; molecular dynamics; molecular marker; non-invasive imaging; novel; novel therapeutics; personalized medicine; predicting response; predictive marker; programs; randomized trial; response; targeted agent; targeted treatment; therapy design; therapy resistant; tool; treatment response; trial design; tumor; tumor eradication; tumor-immune system interactions; virtual

The overarching goal of this program project is to advance the science of individualizing treatment to improve outcomes on the basis of response to therapy. Neoadjuvant chemotherapy (NAC) provides the opportunity to assess response to systemic therapy prior to surgery in women with high risk early breast cancer. The optimal outcome is the complete eradication of tumor, (pathologic complete response (pCR)), which is strongly associated with improved long-term survival and is a surrogate endpoint for accelerated drug approval. Conversely, women with significant residual cancer burden (RCB 2/3) suffer event free survival of less than 60% at 3-5 years. Redirecting therapy in poor responders could dramatically improve breast cancer survival in the highest risk women and minimize toxicities in early responders. The neoadjuvant I-SPY 2 adaptive clinical trial platform, designed to accelerate phase II development of new agents for stage II/III breast cancer is the ideal setting for this work. MRI will serve as a foundation for an integrated residual cancer burden assessment tool (“iRCB”), optimized by tumor subtype and pathway. Two decades of MRI imaging research in the I-SPY program have provided the necessary technology, bioinformatic and statistical approaches, and validation datasets to optimize the iRCB tool to serve as the trigger to redirect to rationally selected, biologically targeted agents. The advances from each project coalesce in Project 1, where we have developed the mechanics of integrating the pieces to determine whether treatment redirection on the basis of pathway abnormalities and avoiding the additional toxicity of chemotherapeutic agents in the setting of complete or poor response leads to better outcomes. Project 2 contributes the tools for the optimization of the iRCB, using advances in imaging methods (diffusion weighted imaging and breast PET) and a longitudinal model that includes molecular data from diagnosis, and an inter-regimen biopsy to confirm absence or presence of disease and accurately classify excellent and poor response (RCB 0 and RCB 2/3, respectively). Project 3 will provide an understanding of the dynamics of the biology of response and treatment resistance, and Project 4 will delineate the rational selection of `second chance” therapies based on the biology and knowledge of agents already or being developed. We will work closely with the FDA over the course of this Program Project to establish the subtype specific thresholds for iRCB. The final result will be an evolution of the existing I-SPY Trial (into “I-SPY2+”) that employs an innovative Sequential Multiple Assignment Randomization Trial (SMART) design to maximize both clinical impact and knowledge generation, while closely reflecting the realities of current clinical practice. Taken together, these projects leverage an established, successful, efficient, and highly innovative clinical trial platform and an experienced, collaborative research team to address a critical clinical issue in breast cancer. The innovative approach employed will mark a milestone in the implementation of personalized medicine in breast cancer and generate an unprecedented view of the molecular evolution of treatment resistance.

该计划项目的总体目标是提高个性化治疗的科学以改善 根据对治疗的反应结果。新辅助化疗（NAC）为 评估高风险早期乳腺癌女性手术前对全身治疗的反应。最佳 结果是肿瘤的完整放射（病理完全反应（PCR）），这是强烈的 与改善的长期生存有关，是加速药物批准的替代终点。 相反，患有严重残留癌症的妇女伯恩（RCB 2/3）遭受的事件生存率少于 3 - 5年的60％。反应者的反应疗法重定向可以大大改善乳腺癌的生存 妇女的风险最高，并最大程度地减少早期响应者的毒性。新辅助I-SPY 2自适应临床 试验平台，旨在加速为II/III期乳腺癌的新代理的II期开发是 这项工作的理想设置。 MRI将作为综合残留癌症伯恩评估的基础 工具（“ IRCB”），由肿瘤亚型和途径优化。 I-SPY中的二十年MRI成像研究 计划提供了必要的技术，生物信息学和统计方法以及验证 数据集优化IRCB工具，以作为触发器的触发器，以重定向到合理选择的，生物学靶向的 代理商。项目1中每个项目联合的进步，我们开发了 整合零件以确定是否基于途径异常和 避免在完全或不良反应的情况下避免化学治疗剂的其他毒性导致 更好的结果。项目2使用成像的进步为优化IRCB的工具提供了贡献 方法（扩散加权成像和母乳喂养）和包括分子数据的纵向模型 从诊断和进行临时活检，以确认缺乏或存在疾病并准确分类 出色和不良反应（分别为RCB 0和RCB 2/3）。项目3将提供对 反应和治疗耐药性生物学的动力学，项目4将描述理性 基于代理的生物学和知识或存在的“第二机​​会”疗法的选择 发达。我们将在该计划项目的过程中与FDA紧密合作以建立子类型 IRCB的特定阈值。最终结果将是现有的I-SPY试验的演变（进入“ I-SPY2+”） 员工创新的连续分配随机试验（智能）设计，以最大化两者 临床影响和知识产生，同时密切反映了当前临床实践的现实。拍摄 这些项目共同利用了既定，成功，高效且高度创新的临床试验 平台和经验丰富的协作研究团队，旨在解决乳腺癌中关键的临床问题。 采用的创新方法将标志着实施个性化医学的里程碑 乳腺癌并产生了对治疗耐药性分子进化的前所未有的观点。