We propose a novel Phase I intra-patient dose-escalation design tailored for multi-cycle immunotherapy settings, in which toxicity at a fixed dose level is clinically expected to decrease over successive treatment cycles. This design was motivated by a phase I trial of CAR T cell therapy, an emerging cellular immunotherapy with established applications in cancer and growing investigation in autoimmune disease. The design is intended for settings in which nonincreasing cycle-specific toxicity assumption is clinically justified. Specifically, we build on the extrapolation property of the modified curve-free Bayesian decision-theoretic (c-CFBD) design for two-agent trials (Xu, et al. 2025), treating treatment cycle as a second dimension. By redefining the partial order, the c-CFBD framework can accommodate the reduction in toxicity across cycles. The proposed design adopts a two-stage structure: an initial accelerated titration stage to rapidly explore dose levels, followed by a c-CFBD stage to improve safety and estimate the cycle-specific maximum tolerated dose sequence. Simulation studies across a range of scenarios demonstrate favorable operating characteristics.

翻译：我们提出了一种新颖的I期患者内剂量递增设计，专为多周期免疫治疗场景定制——在该场景中，固定剂量水平的毒性预计会随着治疗周期推移而临床性降低。该设计源于嵌合抗原受体T细胞疗法（一种新兴细胞免疫治疗，在癌症领域已有成熟应用，并在自身免疫性疾病中开展日益广泛的研究）的I期临床试验。本设计适用于临床确认周期特异性毒性非递增假设的场景。具体而言，我们基于两药物联合试验的改进型免曲线贝叶斯决策理论设计的推演性质（Xu等人，2025年），将治疗周期作为第二维度处理。通过重新定义偏序关系，该框架能够兼容跨周期毒性递减特征。该设计采用两阶段结构：初始加速滴定阶段用于快速探索剂量水平，后续的改进型设计阶段则着力提升安全性并估计周期特异性最大耐受剂量序列。跨多种场景的模拟研究展示了其良好的操作特性。