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：我们提出了一种针对多周期免疫治疗场景的新型I期患者内剂量递增设计，其中固定剂量水平的毒性在临床预期会随着治疗周期推进而降低。该设计源于嵌合抗原受体T细胞疗法的I期临床试验，这是一种新兴的细胞免疫疗法，已在癌症治疗中得到应用，并正逐步扩展至自身免疫性疾病研究。本设计适用于临床可证明“周期特异性毒性非递增假设”的场景。具体而言，我们基于经修改的无曲线贝叶斯决策理论（c-CFBD）设计在双药剂试验中的外推性质（Xu等，2025），将治疗周期视为第二个维度。通过重新定义偏序关系，c-CFBD框架可适应跨周期的毒性降低。所提出的设计采用两阶段结构：初始加速滴定阶段快速探索剂量水平，随后进入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。系列场景的模拟研究表明该设计具有优越的运行特征。