The cross-validated adaptive signature design.

PURPOSE Many anticancer therapies benefit only a subset of treated patients and may be overlooked by the traditional broad eligibility approach to design phase III clinical trials. New biotechnologies such as microarrays can be used to identify the patients that are most likely to benefit from anticancer therapies. However, due to the high-dimensional nature of the genomic data, developing a reliable classifier by the time the definitive phase III trail is designed may not be feasible. EXPERIMENTAL DESIGN Previously, Freidlin and Simon (Clinical Cancer Research, 2005) introduced the adaptive signature design that combines a prospective development of a sensitive patient classifier and a properly powered test for overall effect in a single pivotal trial. In this article, we propose a cross-validation extension of the adaptive signature design that optimizes the efficiency of both the classifier development and the validation components of the design. RESULTS The new design is evaluated through simulations and is applied to data from a randomized breast cancer trial. CONCLUSION The cross-validation approach is shown to considerably improve the performance of the adaptive signature design. We also describe approaches to the estimation of the treatment effect for the identified sensitive subpopulation.