A Novel Phase II Single Arm Hybrid Design to Minimize Trial Duration and Improve the Success Rate of Following Phase III Trial

A Phase II trial is an expeditious and low-cost trial with the primary goal of screening potentially effective agents prior to confirmatory Phase III trial. A lot of Phase III trials fail for lack of significant efficacy despite the success demonstrated in the preceding Phase II trials. This discordance is mainly due to the different endpoints used in Phase II and III trials. While a robust treatment effect on surrogate endpoints is expected to translate into effect on direct endpoints, this is NOT guaranteed. In oncology clinical trials, tumor response (surrogate endpoint) can be determined quickly whereas survival estimation (direct endpoint) requires a long period of follow up. To better bridge the gap between two endpoints, we propose a novel 2-stage single-arm hybrid design for Phase II trials whereby percent of tumor size change is used as an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where survival is estimated to confirm the efficacy of agents. This design can improve trial efficiency and reduce cost by early stopping the evaluation of an ineffective agent based on low percent of tumor size change. The second survival endpoint screening will substantially increase the success rate of follow-up Phase III trial by using the same endpoint. Simulation studies of investigating the performance of our design under different circumstances demonstrated that our novel design has improvement in terms of trial efficiency, trial length, and the success rate of following Phase III trials.