Two-stage design for phase I–II cancer clinical trials using continuous dose combinations of cytotoxic agents

Abstract

We present a two-stage phase I–II design of a combination of two drugs in cancer clinical trials. The goal is to estimate safe dose combination regions with a desired level of efficacy. In stage I, conditional escalation with overdose control is used to allocate dose combinations to successive cohorts of patients and the maximum tolerated dose curve is estimated as a function of Bayes estimates of the model parameters. In stage II, we propose a Bayesian adaptive design for conducting the phase II trial to determine dose combination regions along the maximum tolerated dose curve with a desired level of efficacy. The methodology is evaluated by extensive simulations and application to a real trial.