title: Flexible Phase I Clinical Trials: Allowing for Nonbinary Toxicity Response and Removal of Other Common Limitations.
abstract: Phase I clinical trials are often subject to severe limitations. The most important one is that they typically allow only for binary response-toxic (1) or nontoxic (0)-rather than a range of responses from 0 to 1. They also may not allow a new patient to be treated until results for all previous patients are available. They may assign patients to doses in groups of two or more, rather than individually. They may require the selected dose to be one of a few prespecified doses. The flexible method proposed here addresses these four limitations. It adopts a quasi-Bayesian approach incorporating a logistic dose-response model with two parameters for the mean response. The response at any dose follows a beta distribution, which entails a third parameter. The choice of dose for a patient is based on a utility function that reflects the latest estimates of toxicity and of the variance of the estimate of the maximum tolerated dose (MTD). Simulations show that the method works well, and that a nonbinary toxicity measure leads to a far more accurate MTD estimate than does a binary one.
authors.affiliation: Richard F. Potthoff is Senior Research Scientist, Cancer Statistical Center, and Stephen L. George is Professor of Biostatistics, Department of Biostatistics and Bioinformatics, and Executive Director, Cancer Statistical Center, Duke University Medical Center, Hock Plaza, 2424 Erwin Road, Suite 802, Durham, NC 27705.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potthoff
authors.forename: Stephen L
authors.initials: SL
authors.lastname: George