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Broadening eligibility criteria in cancer trials has been advocated torepresent the true patient population more accurately. While the advantages areclear in terms of generalizability and recruitment, novel dose-finding designsare needed to ensure patient safety. These designs should be able to recommendprecise doses for subpopulations if such subpopulations with different toxicityprofiles exist. While dose-finding designs accounting for patient heterogeneityhave been proposed, all existing methods assume the source of heterogeneity isknown and thus pre-specify the subpopulations or only allow inclusion of a fewpatient characteristics. We propose a precision dose-finding design to addressthe setting of unknown patient heterogeneity in phase I cancer clinical trialswhere eligibility is expanded, and multiple eligibility criteria couldpotentially lead to different optimal doses for patient subgroups. The designoffers a two-in-one approach to dose-finding by simultaneously selectingpatient criteria that differentiate the maximum tolerated dose (MTD) andrecommending the subpopulation-specific MTD if needed, using marginal models tosequentially incorporate patient covariates. Our simulation study compares theproposed design to the naive approach of assuming patient homogeneity and ourdesign recommends multiple doses when heterogeneity exists and a single dosewhen no heterogeneity exists. The proposed dose-finding design addresses thechallenges of broadening eligibility criteria in cancer trials and the desirefor a more precise dose in the context of early phase clinical trials.

Precision Dose-finding Cancer Clinical Trials in the Setting of Broadened Eligibility