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Barnett, Helen ; Boix, Oliver ; Kontos, Dimitris ; Jaki, Thomas

Joint time-to-event partial order continual reassessment method and Joint time-to-event Bayesian logistic regression model: Statistical designs for dual agent phase I/II dose finding studies with late-onset toxicity and activity outcomes

Barnett, Helen, Boix, Oliver, Kontos, Dimitris and Jaki, Thomas (2025) Joint time-to-event partial order continual reassessment method and Joint time-to-event Bayesian logistic regression model: Statistical designs for dual agent phase I/II dose finding studies with late-onset toxicity and activity outcomes. Statistical Methods in Medical Research 35 (1), pp. 186-204.

Date of publication of this fulltext: 24 Feb 2026 13:07
Article
DOI to cite this document: 10.5283/epub.78730


Abstract

Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination, the combination of doses of the two agents that is associated with a pre-specified risk of being unsafe. In a Phase I/II setting, the objective is to find a dose combination that is both safe and active, the Optimal Biological Dose, that ...

Dual agent dose-finding trials study the effect of a combination of more than one agent, where the objective is to find the Maximum Tolerated Dose Combination, the combination of doses of the two agents that is associated with a pre-specified risk of being unsafe. In a Phase I/II setting, the objective is to find a dose combination that is both safe and active, the Optimal Biological Dose, that optimises a criterion based on both safety and activity. Since Oncology treatments are typically given over multiple cycles, both the safety and activity outcome can be considered as late-onset, potentially occurring in the later cycles of treatment. This work proposes two model-based designs for dual-agent dose finding studies with late-onset activity and late-onset toxicity outcomes, the Joint time-to-event (TITE) partial order continual reassessment method and the Joint TITE Bayesian logistic regression model. Their performance is compared alongside a model-assisted comparator in a comprehensive simulation study motivated by a real trial example, with an extension to consider alternative sized dosing grids. It is found that both model-based methods outperform the model-assisted design. Whilst on average the two model-based designs are comparable, this comparability is not consistent across scenarios.



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Details

Item typeArticle
Journal or Publication TitleStatistical Methods in Medical Research
Publisher:Sage
Open Access Type:CC-License
Volume:35
Number of Issue or Book Chapter:1
Page Range:pp. 186-204
Date5 December 2025
InstitutionsInformatics and Data Science > Department Machine Learning & Data Science > Lehrstuhl für Computational Statistics (Prof. Dr. Thomas Jaki)
Identification Number
ValueType
10.1177/09622802251403384DOI
Keywordsdose-finding, late-onset toxicities, late-onset activity, dual agent, phase I trials, model-based
Dewey Decimal Classification000 Computer science, information & general works > 004 Computer science
StatusPublished
RefereedYes, this version has been refereed
Created at the University of RegensburgPartially
URN of the UB Regensburgurn:nbn:de:bvb:355-epub-787306
Item ID78730

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