A modified toxicity probability interval method for dose-finding trials

Abstract

Background Building on earlier work, the toxicity probability interval (TPI) method, we present a modified TPI (mTPI) design that is calibration-free for phase I trials. Purpose Our goal is to improve the trial conduct and provide more effective designs while maintaining the simplicity of the original TPI design. Methods Like the TPI method, the mTPI consists of a practical dose-finding scheme guided by the posterior inference for a simple Bayesian model. However, the new method proposes improved dose-finding decision rules based on a new statistic, the unit probability mass (UPM). For a given interval and a probability distribution, the UPM is defined as the ratio of the probability mass of the interval to the length of the interval. Results The improvement through the use of the UPM for dose finding is threefold: (1) the mTPI method appears to be safer than the TPI method in that it puts fewer patients on toxic doses; (2) the mTPI method eliminates the need for calibrating two key parameters, which is required in the TPI method and is a known difficult issue; and (3) the mTPI method corresponds to the Bayes rule under a decision theoretic framework and possesses additional desirable large- and small-sample properties. Limitation The proposed method is applicable to dose-finding trials with a binary toxicity endpoint. Conclusion The new method mTPI is essentially calibration free and exhibits improved performance over the TPI method. These features make the mTPI a desirable choice for the design of practical trials. Clinical Trials 2010; 7: 653—663. http://ctj.sagepub.com