RESTART trial design: two-stage seamless transition design with operational considerations

Abstract

ABSTRACT Oncology/hematology is a competitive therapeutic area where the landscape is constantly evolving. With regulatory support, many drug developers have spent a lot of resources on the operationalization of innovative clinical trial designs, for example, adaptive Bayesian designs in confirmatory clinical trial settings. While overall survival is considered the gold standard in these designs, it is often not a viable choice in identifying treatment efficacy at a reasonable pace, especially for early-stage therapies. In recent years, several binary response surrogate endpoints have been used for accelerated or conditional approval of novel cancer therapies. Utilizing surrogate endpoints in the study design to predict objective clinical outcomes, such as overall survival, is particularly fundamental in cancer treatment clinical development. This manuscript will investigate logistic and statistical considerations of our proposed RESTART design, a new two-stage, seamless, single- to double-arm Bayesian design. This design could be used for single-arm dose expansion to a randomized confirmatory study. The operating characteristics of the RESTART design are evaluated based on simulations. Future directions and further modifications of this design will also be elaborated.