TITE ‐ LOCRM12 : A Local Continual Reassessment Method for Drug Combination Optimization Based on Late‐Onset Toxicity and Efficacy Outcomes

The primary goal of Phase I/II combination trials is to identify the optimal biological dose combination (OBDC), defined as the dose combination that achieves the highest efficacy while maintaining an acceptable toxicity rate. Several designs have been proposed for such trials. Among them, the local continual reassessment method for Phase I/II trials (LOCRM12) performs well when compared with other model-based methods in most of the scenarios studied. However, LOCRM12 assumes that both toxicity and efficacy outcomes are fully observed before enrolling the next cohort, an assumption that may not hold in real-world settings, where late-onset outcomes are increasingly common with the emergence of novel therapies such as molecularly targeted agents and immunotherapies. To address this limitation, we propose a time-to-event extension of LOCRM12 (TITE-LOCRM12) that accommodates both late-onset toxicity and efficacy outcomes. The local modeling framework, which uses data from neighboring dose combinations, is robust and efficient when data are sparse in complex combination settings. Simulation studies show that the proposed design can achieve a high percentage of correctly selecting the OBDC while maintaining a feasible trial duration.