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，专门针对多周期免疫治疗场景，其中在固定剂量水平下，毒性预计会随着后续治疗周期而临床性地降低。该设计受嵌合抗原受体（CAR）T细胞疗法I期试验的启发，这是一种新兴的细胞免疫疗法，已在癌症中确立应用，并在自身免疫性疾病中逐步开展研究。该设计适用于临床可验证周期特异性毒性非递增假设的场景。具体而言，我们基于改进的无曲线贝叶斯决策理论（c-CFBD）设计在两药试验中的外推性质（Xu等，2025），将治疗周期作为第二维度处理。通过重新定义偏序关系，c-CFBD框架可适应跨周期毒性降低的情况。所提出的设计采用两阶段结构：初始加速滴定阶段以快速探索剂量水平，随后是c-CFBD阶段以改善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显示了有利的操作特性。