Phase II Trials Powered to Detect Tumor Subtypes

Classical phase II trial designs, including adaptive designs, require the prospective characterization of tumors. We propose a 2-stage phase II design that allows for characterization of tumors and selection of a tumor subtype of interest at the conclusion of stage 1. The stage 2 objective is either a classical estimate of the response rate for either the tumor or a subtype, or a formal test of the hypothesis that the response rate for a subtype is greater than the overall response rate. Considering likely scenarios, stage 1 sample sizes approximately range from 20 to 100 with a usual size of 50. This compares with typical classical stage 1 sample sizes of 12 to 30. Total sample sizes range from sizes identical to classical designs (tens to scores) to large sizes typical of phase III trials in metastatic disease (hundreds). Our design is more efficient than previous adaptive designs because it allows for the selection of a tumor subtype of interest on the basis of results from stage 1. It complements classical phase II and phase III designs in which investigators compare different treatments in similar patients and tumors by positioning a treatment as fixed (control) and using tumor subtype as the variable of interest. Clin Cancer Res; 17(17); 5538-45. (C) 2011 AACR.