Precision Bayesian phase I-II dose-finding based on utilities tailored to prognostic subgroups.

A Bayesian phase I-II design is presented that optimizes the dose of a new agent within predefined prognostic subgroups. The design is motivated by a trial to evaluate targeted agents for treating metastatic clear cell renal carcinoma, where a prognostic risk score defined by clinical variables and biomarkers is well established. Two clinical outcomes are used for dose-finding, time-to-toxicity during a prespecified follow-up period, and efficacy characterized by ordinal disease status evaluated at the end of follow-up. A joint probability model is constructed for these outcomes as functions of dose and subgroup. The model performs adaptive clustering of adjacent subgroups having similar dose-outcome distributions to facilitate borrowing information across subgroups. To quantify toxicity-efficacy risk-benefit trade-offs that may differ between subgroups, the objective function is based on outcome utilities elicited separately for each subgroup. In the context of the renal cancer trial, a design is constructed and a simulation study is presented to evaluate the design's reliability, safety, and robustness, and to compare it to designs that either ignore subgroups or run a separate trial within each subgroup.