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

2026-04-28

AI Summary

This study addresses the challenge in multi-cycle immunotherapy where toxicity tends to decrease across treatment cycles despite identical dosing. To tackle this, the authors propose a two-stage intra-patient dose-escalation design that, for the first time, incorporates treatment cycle into a curve-free Bayesian decision framework. By redefining partial ordering to capture the non-increasing trend of toxicity across cycles, and integrating accelerated titration with an enhanced c-CFBD strategy, the method efficiently estimates a cycle-specific sequence of maximum tolerated doses. Simulation studies demonstrate that the proposed design maintains strong safety profiles and high accuracy in identifying optimal doses across diverse toxicity scenarios, substantially improving dose-finding efficiency.

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.

Problem

• dose escalation
• intra-patient
• cycle-specific toxicity
• maximum tolerated dose
• immunotherapy

Innovation

• two-stage design
• intra-patient dose escalation
• cycle-specific toxicity
• curve-free Bayesian decision-theoretic
• CAR T cell therapy