The Modified Combo i3+3 Design for Novel-Novel Combination Dose-Finding Trials in Oncology

Abstract: We consider a modified Ci3+3 (MCi3+3) design for dual-agent dose-finding trials in which both agents are tested on multiple doses. This usually happens when the agents are novel therapies. The MCi3+3 design offers a two-stage or three-stage version, depending on the practical need. The first stage begins with single-agent dose escalation, the second stage launches a model-free combination dose finding for both agents, and optionally, the third stage follows with a model-based design. MCi3+3 aims to maintain a relatively simple framework to facilitate practical application, while also address challenges that are unique to novel-novel combination dose finding. Through simulations, we demonstrate that the MCi3+3 design adeptly manages various toxicity scenarios. It exhibits operational characteristics on par with other combination designs, while offering an enhanced safety profile. The design is motivated and tested for a real-life clinical trial.