A trivariate continual reassessment method for phase I/II trials of toxicity, efficacy, and surrogate efficacy


Bradley P. Carlin, Division of Biostatistics, University of Minnesota, U.S.A.

E-mail: carli002@umn.edu


Recently, many Bayesian methods have been developed for dose finding when simultaneously modeling both toxicity and efficacy outcomes in a blended phase I/II fashion. A further challenge arises when all the true efficacy data cannot be obtained quickly after the treatment so that surrogate markers are instead used (e.g., in cancer trials). We propose a framework to jointly model the probabilities of toxicity, efficacy, and surrogate efficacy given a particular dose. Our trivariate binary model is specified as a composition of two bivariate binary submodels. In particular, we extend the bivariate continual reassessment method (CRM), as well as utilize a particular Gumbel copula. The resulting trivariate algorithm utilizes all the available data at any given time point and can flexibly stop the trial early for either toxicity or efficacy. Our simulation studies demonstrate that our proposed method can successfully improve dosage targeting efficiency and guard against excess toxicity over a variety of true model settings and degrees of surrogacy. Copyright © 2012 John Wiley & Sons, Ltd.