A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up

In phase II oncology trials, the use of new cytostatic drugs raises some questions regarding the endpoint. Time-to-event endpoints such as Progression-Free Survival have been recommended and led to new designs. In 2003, Case and Morgan proposed a design based on the comparison of the cumulative hazards at a clinically relevant timepoint. In 2013, Kwak proposed a design based on the one-sample log-rank test. If all the patients are followed from their entry time to the analysis date, the Kwak and Jung’s design leads to a smaller sample size as compared to the Case-Morgan’s design. However, the Case and Morgan’s design requires less information since it only needs to follow every patient during a fixed interval of time. We propose a trade-off between these two approaches that corresponds to an adaptation of Kwak and Jung’s design when the follow-up is expected to be restricted. Our proposal is based on the one-sample log-rank test as the Kwak and Jung’s design but it uses the same follow-up information as the Case-Morgan’s design. Simulation study shows that our proposal allows reducing the sample size as compared to the Case-Morgan’s design (median difference of 23% [15%-33%]). Type I and type II error rates are close to their nominal rates planned in the protocol. A real phase II clinical trial in cervical cancer illustrated the interest of this new design. Thus, our proposal can be recommended as an alternative to the Kwak’s design when patients’ follow-up is restricted.