Abstract: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.
From: Dehua Bi [view email]
[v1]
Wed, 29 Apr 2026 03:59:52 UTC (1,419 KB)
[v2]
Mon, 4 May 2026 20:46:35 UTC (1 KB) (withdrawn)
[v3]
Fri, 12 Jun 2026 17:51:48 UTC (4,456 KB)
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