Evolution of Phase II Oncology Trial Design: from Single Arm to Master Protocol.

Abstract

The recent development of novel anticancer treatments with diverse mechanisms of action has accelerated the detection of treatment candidates tremendously. The rapidly changing drug development landscapes and the high failure rates in Phase III trials both underscore the importance of more efficient and robust phase II designs. The goals of phase II oncology studies are to explore the preliminary efficacy and toxicity of the investigational product and to inform future drug development strategies such as go/no-go decisions for phase III development, or dose/indication selection. These complex purposes of phase II oncology designs call for efficient, flexible, and easy-to-implement clinical trial designs. Therefore, innovative adaptive study designs with the potential of improving the efficiency of the study, protecting patients, and improving the quality of information gained from trials have been commonly used in Phase II oncology studies. Although the value of adaptive clinical trial methods in early phase drug development is generally well accepted, there is no comprehensive review and guidance on adaptive design methods and their best practice for phase II oncology trials. In this paper, we review the recent development and evolution of phase II oncology design, including frequentist multistage design, Bayesian continuous monitoring, master protocol design, and innovative design methods for randomized phase II studies. The practical considerations and the implementation of these complex design methods are also discussed.