The Generalized 3+3 (G3+3) Design for Phase I Dose-Finding Trials

Abstract

PURPOSE We propose and demonstrate the feasibility and desirability of a novel model-free dose-finding design for phase I clinical trials. METHODS The Generalized 3+3 (G3+3) design uses a set of simple rules summarized as follows: For 3 or 6 patients at a dose, apply the 3+3 design for making dosing decisions. For other numbers, if the observed toxicity rate (OTR) is less than 0.2, escalate to the next higher dose; if the OTR is greater than 0.29, de-escalate to the next lower dose; otherwise, stay at the current dose. RESULTS The G3+3 design is the only design that can replicate the decisions of the 3+3 design for 3 or 6 patients among the popular designs compared like BOIN and i3+3. G3+3 generates desirable decisions when the number of patients treated is not 3 or 6, like the popular designs. Computer simulation verifies the superior operating characteristics of the G3+3 design. CONCLUSION The G3+3 design generalizes the popular 3+3 design so that desirable decisions can be made for any number of patients at a dose. Since G3+3 does not rely on statistical models, is simple and transparent, and can be implemented without a software tool, it is expected to facilitate and enhance modern phase I dose-finding trials and early-phase drug development.