Improved adaptive randomization strategies for a seamless Phase I/II dose-finding design.

In this article, we propose and evaluate three alternative randomization strategies to the adaptive randomization (AR) stage used in a seamless Phase I/II dose-finding design. The original design was proposed by Wages and Tait in 2015 for trials of molecularly targeted agents in cancer treatments, where dose-efficacy assumptions are not always monotonically increasing. Our goal is to improve the design's overall performance regarding the estimation of optimal dose as well as patient allocation to effective treatments. The proposed methods calculate randomization probabilities based on the likelihood of every candidate model as opposed to the original design which selects the best model and then randomizes doses based on estimations from the selected model. Unlike the original method, our proposed adaption does not require an arbitrarily specified sample size for the adaptive randomization stage. Simulations are used to compare the proposed strategies and a final strategy is recommended. Under most scenarios, our recommended method allocates more patients to the optimal dose while improving accuracy in selecting the final optimal dose without increasing the overall risk of toxicity.