Longitudinal design for phase I clinical trials using the continual reassessment method.

The goal of phase I clinical trials is to estimate the maximum tolerated dose (MTD), the highest dose at which a specified probability of toxic response is not exceeded. However, this is not the only piece of information that is useful for the design of phase II and phase III clinical trials. Information on cumulative toxicity is important as well. To study the effect of cumulative toxicity in patients, it is necessary to examine how patients respond to multiple-dose administrations. To this end, we propose a longitudinal dose-response model that accommodates this concern, which is motivated from clearance-rate considerations and from a model proposed by Simon et al. To appropriately titrate an individual's dosage at each time period, we also propose an updating mechanism based on the Bayesian paradigm. We select individual and group MTDs using Legedza and Ibrahim's extension of O'Quigley et al. 's Continual Reassessment Method. Simulations are described to demonstrate the usefulness of our proposal. Control Clin Trials 2000;21:574-588