A STRATEGY FOR DOSE-FINDING AND SAFETY MONITORING BASED ON EFFICACY AND ADVERSE OUTCOMES IN PHASE I II CLINICAL-TRIALS/

We propose a design strategy for single-arm clinical trials in which t he goals are to find a dose of an experimental treatment satisfying bo th safety and efficacy requirements, treat a sufficiently large number of patients to estimate the rates of these events at the selected dos e with a given reliability, and stop the trial early if it is Likely t hat no dose is both safe and efficacious. Patient outcome is character ized by a trinary ordinal variable accounting for both efficacy and to xicity. Like Thall, Simon, and Estey (1995, Statistics in Medicine 14, 357-379), we use Bayesian criteria to generate decision rules while r elying on frequentist criteria obtained via simulation to determine a design parameterization with good operating characteristics. The strat egy is illustrated by application to a bone marrow transplantation tri al for hematologic malignancies and a trial of a biologic agent for ma lignant melanoma.