Seamless Phase I/II Designs for Precision Medicine Trials

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In drug development, one key attribute is to select inefficacious and/or unsafe treatments which should be excluded inearly-phase clinical trials. Discrete traditional designs, usually incompletely considering efficacy data in phase I andtoxicity data in phase II, can lead to the misspecification of the appropriate dose(s). By consolidating phases I and II intoa single study and modelling both efficacy and toxicity, seamless phase I/II designs have gained increasing attention toimprove the efficiency and accuracy of drug development. With growing interest in developing immunotherapies andmolecularly targeted agents (MTAs) in the era of precision medicine, the principal objective of seamless phase I/IIdesigns becomes to estimate an optimal biological dose (OBD). Such treatments have raised new statistical challenges,including non-monotonic dose-response relationships, late-onset outcomes, and heterogeneity of participants in clinicaltrials. This project aims to research seamless phase I/II designs for precision medicine trials: First, improve on the so calleddose-escalation followed by expansion cohorts (DE-EC) method using Bayesian hierarchical modelling. Next,consider trials evaluating MTAs, where the monotonic dose-response assumption does not hold. Ordinary differentialequations may be used to fit the curves. Finally, I plan to model multinomial outcomes (e.g., toxicity, no toxicity butefficacy) rather than bivariate binary toxicity and efficacy.