A new statistical method for dose-finding based on efficacy and toxicity in early phase clinical trials

Most statistical methods for dose-finding in phase I clinical trials determ ine a maximum tolerable dose based on toxicity while ignoring efficacy. Mos t phase II designs assume that an acceptable dose has been determined and a im to estimate treatment efficacy, possibly with early stopping rules for s afety monitoring. The purpose of this paper is to describe a new statistica l strategy for dose-finding in single-arm clinical trials where patient out come is characterized in terms of both response and toxicity. The strategy, which may be considered a phase I/II hybrid, was first proposed by Thall a nd Russell [1] and subsequently modified by Thall [2]. The underlying mathe matical model expresses the probabilities of response and toxicity as inter dependent functions of dose. The method is based on fixed standards for the minimum probability of response and the maximum probability of toxicity ap propriate for the particular trial. The best acceptable dose is chosen for each successive patient cohort adaptively, based on the fixed standards and the dose-outcome data from patients treated previously in the trial. The s cientific goals are to select one best acceptable dose for future patients and to estimate the response and toxicity probabilities at that dose, or to stop the trial early if it becomes sufficiently unlikely that any dose is both safe and efficacious. An application of the method to a trial of donor lymphocyte infusion as salvage therapy for chemo-refractory AML/MDS patien ts is described. To illustrate the method's flexibility and potential bread th of application, two additional examples are provided, including a hypoth etical trial in which a 5% response rate is of interest.