TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design
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arXiv
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| Main Authors: | , , , , , , , , |
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| Format: | Preprint |
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2026
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| _version_ | 1866910190381563904 |
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| author | Bi, Dehua Good, Zina Ryan, Katherine Heitzeneder, Sabine Tamaresis, John S. Lowskey, Robert Monje, Michelle Mackall, Crystal Lu, Ying |
| author_facet | Bi, Dehua Good, Zina Ryan, Katherine Heitzeneder, Sabine Tamaresis, John S. Lowskey, Robert Monje, Michelle Mackall, Crystal Lu, Ying |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2604_26272 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design Bi, Dehua Good, Zina Ryan, Katherine Heitzeneder, Sabine Tamaresis, John S. Lowskey, Robert Monje, Michelle Mackall, Crystal Lu, Ying Methodology 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. |
| title | TWICEBEE: A Two-stage Intra-patient Curve-free Bayesian Decision-Theoretic Dose Escalation Design |
| topic | Methodology |
| url | https://arxiv.org/abs/2604.26272 |