An adaptive dose-finding design incorporating both toxicity and efficacy

Novel therapies are challenging the standards of drug development. Agents with specific biologic targets and limited toxicity require novel designs to determine doses to be taken forward into larger studies. In this paper, we describe an approach that incorporates both toxicity and efficacy data into the estimation of the biologically optimal dose of an agent in a phase I trial. The approach is based on the flexible continuation-ratio model, and uses straightforward optimal dose selection criteria. Dose selection is based on all patients treated up until that time point, using a continual reassessment method approach. Dose-outcome curves considered include monotonically increasing, monotonically decreasing, and unimodal curves. Our simulation studies demonstrate that the proposed design, which we call TriCRM, has favourable operating characteristics. Copyright (c) 2005 John Wiley & Sons, Ltd.