A model-assisted design for phase I oncology drug combination trials incorporating backfill

Abstract

Historically, phase I oncology trials were designed with the focus to find the highest tolerable dose. However, given the FDA's acknowledgment that the highest tolerable dose might not be the dose which is optimal biologically, there is an increased emphasis the development of designs that explore the dose-toxicity and dose-efficacy relationship. Backfill designs have emerged as a popular response to address this need by allocating participants to doses deemed safe while awaiting participants outcomes. Previous designs have explored how to assign participants to doses in backfill designs in a rigorous manner while providing simplicity and performance (a class of designs known as model-assisted) for single agents. Still, a research gap exists in the lack of model-assisted backfill designs for drug combinations. Frequently, the combinations two of cancer agents are explored in phase I trials, with the goal of identifying the highest tolerable combination. This paper incorporates and extends methodology based on previous model-assisted backfill designs to provide clinicians with a simple-to-use backfill design for phase I drug combination trials.