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推进个体化治疗的科学，以改善 新辅助化疗（NAC）提供了基于治疗​​反应的结果。 评估患有高风险早期乳腺癌的女性在手术前对全身治疗的反应。 结果是肿瘤的完全根除（病理完全缓解（pCR）），这是强烈的 与改善长期生存相关，是加速药物批准的替代终点。 在网上，具有显着残余癌症负担（RCB 2/3）的女性的无事件生存率低于 3-5 年，对反应不佳者进行重新定向治疗可以显着提高乳腺癌患者的生存率。 新辅助 I-SPY 2 适应性临床。 试验平台旨在加速 II/III 期乳腺癌新药的 II 期开发 这项工作的理想环境将作为综合残留癌症负担评估的基础。 工具（“iRCB”），根据肿瘤亚型和途径进行了二十年的 I-SPY MRI 成像研究优化。 计划提供了必要的技术、生物信息学和统计方法以及验证 数据集来优化 iRCB 工具，以作为重定向到合理选择的生物学目标的触发器 每个项目的进步都集中在项目 1 中，我们在其中开发了以下机制： 整合各个部分以确定是否根据途径异常和 在完全或不良反应的情况下避免化疗药物的额外毒性会导致 项目 2 利用成像技术的进步提供了优化 iRCB 的工具。 方法（弥散加权成像和乳腺 PET）和包含分子数据的纵向模型 通过诊断和跨方案活检来确认是否存在疾病并准确分类 优秀和较差的反应（分别为 RCB 0 和 RCB 2/3）。项目 3 将提供对 反应和治疗抵抗的生物学动态，项目 4 将描述合理的 根据已经或正在使用的药物的生物学和知识选择“第二次机会”疗法 我们将在该计划项目过程中与 FDA 密切合作，以确定该亚型。 iRCB 的具体阈值将是现有 I-SPY 试验的演变（变成“I-SPY2+”）： 采用创新的序贯多重分配随机试验 (SMART) 设计，最大限度地提高 临床影响和知识生成，同时密切反映当前临床实践的现实。 这些项目共同利用了成熟、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致力于解决乳腺癌的关键临床问题。 所采用的创新方法将标志着个性化医疗实施的一个里程碑 乳腺癌并产生了治疗耐药性分子进化的前所未有的观点。