uTPI-Comb: an optimal Bayesian dose-allocation method in two-agent phase Ⅰ/Ⅱ clinical trials

Finding the optimal dose combination in two-agent dose-finding trials is challenging due to limited sample sizes and the extensive range of potential doses. Unlike traditional chemotherapy or radiotherapy, which primarily focuses on identifying the maximum tolerated dose (MTD), therapies involving targeted and immune agents facilitate the identification of an optimal biological dose combination (OBDC) by simultaneously evaluating both toxicity and efficacy. Currently, most approaches to determining the OBDC in the literature are model-based and require complex model fittings, making them cumbersome and challenging to implement. To address these challenges, we developed a novel model-assisted approach called uTPI-Comb. This approach refines the established utility-based toxicity probability interval design by integrating a strategically devised zone-based local and global candidate set searching strategy, which can effectively optimize the decision-making process for two-agent dose escalation or de-escalation in drug combination trials. Extensive simulation studies demonstrate that the uTPI-Comb design speeds up the dose-searching process and provides substantial improvements over existing model-based methods in determining the optimal biological dose combinations.