Stopping rules for phase I clinical trials with dose expansion cohorts.

Abstract

Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample size of these designs. However, even with a small sample size, this paper shows that easily implementable stopping rules can terminate dose-escalation early with minimal loss to the accuracy of maximum tolerated dose estimation. These stopping rules are developed when the goal is to identify one or two dose levels, as the maximum tolerated dose and co-maximum tolerated dose. In oncology, this latter goal is frequently considered when the study includes dose-expansion cohorts, which are used to further estimate and compare the safety and efficacy of one or two dose levels. As study protocols do not typically halt accrual between escalation and expansion, early termination is of clinical importance as it either allows for additional patients to be treated as part of the dose expansion cohort to obtain more precise estimates of the study endpoints or allows for an overall reduction in the total sample size.