The Ci3+3 Design for Dual-Agent Combination Dose-Finding Clinical Trials

We propose a rule-based statistical design for combination dose-finding trials with two agents. The Ci3+3 design is an extension of the i3+3 design with simple decision rules comparing the observed toxicity rates and equivalence intervals that define the maximum tolerated dose combination. Ci3+3 consists of two stages to allow fast and efficient exploration of the dose-combination space. Statistical inference is restricted to a beta-binomial model for dose evaluation, and the entire design is built upon a set of fixed rules. We show via simulation studies that the Ci3+3 design exhibits similar and comparable operating characteristics to more complex designs utilizing model-based inferences. We believe that the Ci3+3 design may provide an alternative choice to help simplify the design and conduct of combination dose-finding trials in practice.