Practical model-based dose-finding in phase I clinical trials: methods based on toxicity.

We describe two practical, outcome-adaptive statistical methods for dose-finding in phase I clinical trials. One is the continual reassessment method and the other is based on a logistic regression model. Both methods use Bayesian probability models as a basis for learning from the accruing data during the trial, choosing doses for successive patient cohorts, and selecting a maximum tolerable dose (MTD). These methods are illustrated and compared to the conventional 3+3 algorithm by application to a particular trial in renal cell carcinoma. We also compare their average behavior by computer simulation under each of several hypothetical dose-toxicity curves. The comparisons show that the Bayesian methods are much more reliable than the conventional algorithm for selecting an MTD, and that they have a low risk of treating patients at unacceptably toxic doses.