Adaptive Bayesian phase I clinical trial designs for estimating the maximum tolerated doses for two drugs while fully utilizing all toxicity information

• Type of Material: Article
• Authors: Yuzi Zhang, Emory University; Michael Kutner, Emory University; Zhengjia Chen, Emory University
• Language: English
• Date: 2021-05-10
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Wiley-VCH GmbH
• Final Published Version (URL): http://dx.doi.org/10.1002/bimj.202000142
• Title of Journal or Parent Work: BIOMETRICAL JOURNAL
• Volume: 63
• Issue: 7
• Start Page: 1476
• End Page: 1492
• Keywords: SCORE; continuous toxicity response; Statistics & Probability; BURDEN; Life Sciences & Biomedicine; ESCALATION; INTERVAL DESIGN; cancer phase I clinical trial; quasi‐ COMBINATIONS; maximum tolerated dose curve; Mathematics; Science & Technology; Mathematical & Computational Biology; escalation with overdose control; drug combination; AGENTS; ONCOLOGY; Physical Sciences

Abstract

The combined treatments with multiple drugs are very common in the contemporary medicine, especially for medical oncology. Therefore, we developed a Bayesian adaptive Phase I clinical trial design entitled escalation with overdoing control using normalized equivalent toxicity score for estimating maximum tolerated dose (MTD) contour of two drug combination (EWOC-NETS-COM) used for oncology trials. The normalized equivalent toxicity score (NETS) as the primary endpoint of clinical trial is assumed to follow quasi-Bernoulli distribution and treated as quasi-continuous random variable in the logistic linear regression model which is used to describe the relationship between the doses of the two agents and the toxicity response. Four parameters in the dose–toxicity model were re-parameterized to parameters with explicit clinical meanings to describe the association between NETS and doses of two agents. Noninformative priors were used and Markov chain Monte Carlo was employed to update the posteriors of the four parameters in dose–toxicity model. Extensive simulations were conducted to evaluate the safety, trial efficiency, and MTD estimation accuracy of EWOC-NETS-COM under different scenarios, using the EWOC as reference. The results demonstrated that EWOC-NETS-COM not only efficiently estimates MTD contour of multiple drugs but also provides better trial efficiency by fully utilizing all toxicity information.