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A Bayesian adaptive design for dual-agent phase I-II oncology trials integrating efficacy data across stages.

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Published version
Peer-reviewed

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Abstract

Combination of several anticancer treatments has typically been presumed to have enhanced drug activity. Motivated by a real clinical trial, this paper considers phase I-II dose finding designs for dual-agent combinations, where one main objective is to characterize both the toxicity and efficacy profiles. We propose a two-stage Bayesian adaptive design that accommodates a change of patient population in-between. In stage I, we estimate a maximum tolerated dose combination using the escalation with overdose control (EWOC) principle. This is followed by a stage II, conducted in a new yet relevant patient population, to find the most efficacious dose combination. We implement a robust Bayesian hierarchical random-effects model to allow sharing of information on the efficacy across stages, assuming that the related parameters are either exchangeable or nonexchangeable. Under the assumption of exchangeability, a random-effects distribution is specified for the main effects parameters to capture uncertainty about the between-stage differences. The inclusion of nonexchangeability assumption further enables that the stage-specific efficacy parameters have their own priors. The proposed methodology is assessed with an extensive simulation study. Our results suggest a general improvement of the operating characteristics for the efficacy assessment, under a conservative assumption about the exchangeability of the parameters a priori.

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Keywords

drug combination, information borrowing, meta-analytic-combined, phase I-II, seamless designs, Humans, Bayes Theorem, Computer Simulation, Dose-Response Relationship, Drug, Medical Oncology, Neoplasms, Research Design, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic

Journal Title

Biom J

Conference Name

Journal ISSN

0323-3847
1521-4036

Volume Title

Publisher

Wiley
Sponsorship
Cancer Research UK (RCCPDF\100008)