Advanced Utilization of Intermediate Endpoints for Making Optimized Cost-Effective Decisions in Seamless Phase II/III Oncology Trials

Abstract

Traditional oncology trials are usually expensive, take a long time, and suffer from high failure rates. With cancer being one of the leading causes of death worldwide, there is an increasingly urgent need to improve current oncology drug development so that more innovative therapies can become available to cancer patients much sooner. Adaptive seamless Phase II/III designs hold great promise as they can accelerate the decision-making by eliminating the white space between Phase II and Phase III. Most literature discusses trial adaptions by using the same endpoint for both trial stages. However, in oncology drug development, the Phase III endpoint is usually a clinical endpoint, that is, overall survival, which takes long time to observe. Use of the clinical endpoint for adaptive decision may delay the trial adaptation and make seamless Phase II/III designs less appealing. This is one of the main reasons why such designs are less used in practice in oncology drug development. In this article, we would like to address the following two issues: (1) how to incorporate intermediate endpoint (e.g., progression-free survival or objective response rate) data into the decision criteria; (2) how to derive objective adaption criteria from a benefit-cost ratio perspective to streamline the decision-making process. This work is based on two real design examples in the oncology therapeutic area: an operationally seamless design with dose-selection and a statistically seamless 2-in-1 design. However, the general approach is applicable to various other therapeutic areas.