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

I SPY 2.2 试验：演变为影像学和分子生物标志物反应指导的适应性序贯治疗以优化乳腺癌结果

• 批准号: 10628608
• 负责人: LAURA J ESSERMAN
• 金额: $ 268.95万
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628608
• 关键词: Acceleration; Adjuvant Therapy; Advocacy; Advocate; Bioinformatics; Biological; Biological Markers; Biology; Biostatistics Core; Blood; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Magnetic Resonance Imaging; Cessation of life; Circulation; Clinical Drug Development; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Communication; Dedications; Development; Discipline; Distant; Drug Combinations; Drug Targeting; Early treatment; Elements; Enrollment; Goals; Image; Immune; Immune response; In complete remission; Individual; Information Systems; Information Technology; Infrastructure; Laboratories; Leadership; Malignant Neoplasms; Measures; Molecular; Morbidity - disease rate; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II/III Trial; Population; Process; Productivity; Quality of life; Randomized; Recurrence; Regimen; Research; Research Personnel; Residual Neoplasm; Resistance; Resource Sharing; Resources; Sampling; Selection for Treatments; Sequential Treatment; Site; Speed; System; Systems Integration; Testing; Therapeutic; Time; Toxic effect; Translating; Translations; Treatment Protocols; Treatment outcome; Tumor Burden; Waiting Lists; Woman; Work; cancer type; clinical practice; data resource; design; drug development; druggable target; effective therapy; experience; high risk; image archival system; imaging biomarker; improved; improved outcome; individual patient; individualized medicine; innovation; insight; intrinsic motivation; malignant breast neoplasm; molecular marker; multidisciplinary; next generation; non-invasive imaging; novel; novel therapeutics; operation; personalized care; personalized medicine; precision medicine; predicting response; predictive marker; predictive modeling; prevent; programs; response; response biomarker; side effect; success; targeted agent; targeted biomarker; targeted treatment; treatment response; treatment strategy; trial design; tumor; unnecessary treatment

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.

I-SPY计划项目在先进的临床试验设计中推进个性化治疗的目标 这有助于不断改进成果。在这个项目中，我们专注于妇女与阶段2和3分子 高风险的早期乳腺癌患者，其快速进展和死亡的风险最高。I-SPY 2.2程序项目 使我们能够产生一种以患者为中心的临床药物开发方法， 在试验背景下，根据治疗反应，通过递增或递减治疗进行靶向治疗 有效评估新型潜在一线药物和治疗方案。在这一过程中形成的经验教训和见解 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-SPY 2.2计划项目的继续将为发现研究提供资源， 将增加完全缓解（pCR）并防止转移。拟议的四个项目和三个共享资源核心 将使我们能够创建将来自肿瘤的多种生物标志物分析物和在肿瘤中评估的衍生物相结合的策略。 循环，以建立更好的新辅助治疗中缺乏应答和不良结局的预测模型 并进一步确定残留疾病中的“可用药”靶点，以减轻耐药性。I-SPY计划和 实际上，该项目建立了一个持续改善乳腺癌治疗结果的系统，使我们能够 推动乳腺癌精准医疗的进展，重要的是，使用高度以患者为中心的框架。迭代 这一过程将通过利用生物学见解，改善反应， 预测性生物标志物，以及疗效和对生活质量影响的整合。这些元素的结合 将挽救生命，降低发病率，并为改善个性化和转化为临床实践奠定基础。 在I-SPY 2.2计划项目的过去5年中，我们实现了所有既定目标，创建并实施了（6月 2022）一个新的，创新的试验设计，既测试新的药物和治疗过程中的个性化护理。在 在接下来的五年里，我们将反复完善流程，通过尽早降低 在成功的情况下进行治疗，在最小反应的情况下进行早期升级治疗， 在建立和完善定量乳腺MRI作为反应评估的生物标志物方面的创新。我们将使用 在前五年开发的综合分子和免疫反应预测亚型， 靶向药物最初不使用标准化疗药物，但如果反应不充分，则依次使用。我们将 基于我们开发的改进的、反应预测的亚型随机治疗，以测试它们精确地 分配治疗。我们将使用顺序多重分配方法（SMART）来确定 治疗，并使用框架整合无缝的2/3期试验，这将加快获得最有效的过程， 在最短的时间内为妇女提供毒性最小的治疗策略。拟议方案项目的基础设施 紧密结合的、经验丰富的多学科团队致力于实现该计划的目标，这将使我们能够 实现我们的目标，并影响高危乳腺癌妇女的生活。

项目成果

Impact of Body Mass Index on Pathological Response after Neoadjuvant Chemotherapy: Results from the I-SPY 2 trial.

体重指数对新辅助化疗后病理反应的影响：I-SPY 2 试验的结果。

• DOI: 10.21203/rs.3.rs-2588168/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Wang,Haiyun;Yee,Douglas;Potter,David;Jewett,Patricia;Yau,Christina;Beckwith,Heather;Watson,Allison;O'Grady,Nicholas;Wilson,Amy;Brain,Susie;Pohlmann,Paula;Blaes,Anne
• 通讯作者: Blaes,Anne

Diffusion-Weighted MRI for Predicting Pathologic Complete Response in Neoadjuvant Immunotherapy.

• DOI: 10.3390/cancers14184436
• 发表时间: 2022-09-13
• 期刊: Cancers
• 影响因子: 5.2

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

• DOI: 10.1038/s41523-021-00337-2
• 发表时间: 2021-10-05
• 期刊: NPJ breast cancer
• 影响因子: 5.9
• 作者: Yee D;Isaacs C;Wolf DM;Yau C;Haluska P;Giridhar KV;Forero-Torres A;Jo Chien A;Wallace AM;Pusztai L;Albain KS;Ellis ED;Beckwith H;Haley BB;Elias AD;Boughey JC;Kemmer K;Yung RL;Pohlmann PR;Tripathy D;Clark AS;Han HS;Nanda R;Khan QJ;Edmiston KK;Petricoin EF;Stringer-Reasor E;Falkson CI;Majure M;Mukhtar RA;Helsten TL;Moulder SL;Robinson PA;Wulfkuhle JD;Brown-Swigart L;Buxton M;Clennell JL;Paoloni M;Sanil A;Berry S;Asare SM;Wilson A;Hirst GL;Singhrao R;Asare AL;Matthews JB;Hylton NM;DeMichele A;Melisko M;Perlmutter J;Rugo HS;Fraser Symmans W;Van't Veer LJ;Berry DA;Esserman LJ
• 通讯作者: Esserman LJ

Radiomic tumor phenotypes augment molecular profiling in predicting recurrence free survival after breast neoadjuvant chemotherapy.

• DOI: 10.1038/s43856-023-00273-1
• 发表时间: 2023-03-30
• 期刊: COMMUNICATIONS MEDICINE
• 作者: Chitalia, Rhea;Miliotis, Marios;Jahani, Nariman;Tastsoglou, Spyros;McDonald, Elizabeth S;Belenky, Vivian;Cohen, Eric A;Newitt, David;Van't Veer, Laura J;Esserman, Laura;Hylton, Nola;DeMichele, Angela;Hatzigeorgiou, Artemis;Kontos, Despina
• 通讯作者: Kontos, Despina

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

• DOI: 10.1038/s41523-022-00493-z
• 发表时间: 2022-12-01
• 期刊: NPJ BREAST CANCER
• 影响因子: 5.9
• 作者: Lang, Julie E.;Forero-Torres, Andres;Yee, Douglas;Yau, Christina;Wolf, Denise;Park, John;Parker, Barbara A.;Chien, A. Jo;Wallace, Anne M.;Murthy, Rashmi;Albain, Kathy S.;Ellis, Erin D.;Beckwith, Heather;Haley, Barbara B.;Elias, Anthony D.;Boughey, Judy C.;Yung, Rachel L.;Isaacs, Claudine;Clark, Amy S.;Han, Hyo S.;Nanda, Rita;Khan, Qamar J.;Edmiston, Kristen K.;Stringer-Reasor, Erica;Price, Elissa;Joe, Bonnie;Liu, Minetta C.;Brown-Swigart, Lamorna;Petricoin, Emanuel F.;Wulfkuhle, Julia D.;Buxton, Meredith;Clennell, Julia L.;Sanil, Ashish;Berry, Scott;Asare, Smita M.;Wilson, Amy;Hirst, Gillian L.;Singhrao, Ruby;Asare, Adam L.;Matthews, Jeffrey B.;Melisko, Michelle;Perlmutter, Jane;Rugo, Hope S.;Symmans, W. Fraser;van't Veer, Laura J.;Hylton, Nola M.;DeMichele, Angela M.;Berry, Donald A.;Esserman, Laura J.
• 通讯作者: Esserman, Laura J.