The I-SPY2 phase 2 clinical trial is a long-running platform trial that evaluates neoadjuvant treatments for locally advanced breast cancer, assigning subjects to novel agents using response-adaptive randomization. Recently, I-SPY2 was reconfigured as a sequential multiple assignment randomized trial (SMART), with up to three stages of therapy. At the first stage, a subject is assigned to a tumor-subtype-specific therapy. If the subject fails to show a satisfactory response to the initial therapy, the subject is assigned to a second subtype-specific therapy, and receives a third, rescue therapy if response is still not achieved. The I-SPY2 SMART thus evaluates entire treatment regimes that recommend therapies at every stage if needed. The transition of I-SPY2 to a SMART required development of a response-adaptive randomization scheme that updates randomization probabilities at each stage, aligned with the goal of maximizing the number of subjects who achieve a pathological complete response (pCR). We present the details of our novel approach, which uses Thompson sampling to update randomization probabilities based on the posterior probability that treatments are part of the optimal regime. Empirical studies that demonstrate that it improves within-trial regime-specific pCR rates and recommends optimal regimes at rates similar to uniform, nonadaptive randomization.

翻译：I-SPY2 二期临床试验是一项长期运行的平台试验，旨在评估局部晚期乳腺癌的新辅助治疗方案，采用响应自适应随机化方法将受试者分配至新型药物组。近期，I-SPY2 被重构为序列多阶段随机化试验（SMART），最多包含三个治疗阶段。在第一阶段，受试者被分配至肿瘤亚型特异性治疗方案。若受试者对初始治疗未表现出满意响应，则进入第二阶段接受另一种亚型特异性治疗；若仍未达到响应标准，将接受第三阶段的挽救治疗。因此，I-SPY2 SMART 评估的是包含必要时各阶段治疗建议的完整治疗方案体系。为实现向 SMART 的转型，需要开发一种响应自适应随机化方案，该方案能在每个阶段更新随机化概率，其核心目标是最大化实现病理完全缓解（pCR）的受试者数量。本文详细阐述了这一创新方法：采用汤普森采样技术，基于治疗方案属于最优方案体系的后验概率来更新随机化概率。实证研究表明，该方法能提升试验内特定方案体系的 pCR 率，并以与均匀非自适应随机化相当的效率推荐最优治疗方案。