TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design

Dehua Bi; Katherine Ryan; Sabine Heitzeneder; Zina Good; John S. Tamaresis; Robert Lowsky; Michelle Monje; Crystal Mackall; Ying Lu

arXiv · 2604.26272

TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design

Dehua Bi·Katherine Ryan·Sabine Heitzeneder·Zina Good·John S. Tamaresis·Robert Lowsky·Michelle Monje·Crystal Mackall·Ying Lu

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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.

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Dehua Bi, Katherine Ryan, Sabine Heitzeneder, Zina Good, John S. Tamaresis, Robert Lowsky, Michelle Monje, Crystal Mackall, Ying Lu. 2026-04-29. TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design. https://arxiv.org/abs/2604.26272

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