STEIN: A simple toxicity and efficacy interval design for seamless phase I/II clinical trials.

Seamless phase I/II dose-finding trials are attracting increasing attention nowadays in early-phase drug development for oncology. Most existing phase I/II dose-finding methods use sophisticated yet untestable models to quantify dose-toxicity and dose-efficacy relationships, which always renders them difficult to implement in practice. To simplify the practical implementation, we extend the Bayesian optimal interval design from maximum tolerated dose finding to optimal biological dose finding in phase I/II trials. In particular, optimized intervals for toxicity and efficacy are respectively derived by minimizing probabilities of incorrect classifications. If the pair of observed toxicity and efficacy probabilities at the current dose is located inside the promising region, we retain the current dose; if the observed probabilities are outside of the promising region, we propose an allocation rule by maximizing the posterior probability that the response rate of the next dose falls inside a prespecified efficacy probability interval while still controlling the level of toxicity. The proposed interval design is model-free, thus is suitable for various dose-response relationships. We conduct extensive simulation studies to demonstrate the small- and large-sample performance of the proposed method under various scenarios. Compared to existing phase I/II dose-finding designs, not only is our interval design easy to implement in practice, but it also possesses desirable and robust operating characteristics.