Escalation with overdose control for phase I drug-combination trials

Abstract

The escalation with overdose control (EWOC) method is a popular modelbased dose finding design for phase I clinical trials. Dose finding for combined drugs has grown rapidly in oncology drug development. A two-dimensional EWOC design is proposed for dose finding with two agents in combination based on a four-parameter logistic regression model. During trial conduct, the posterior distribution of the maximum tolerated dose (MTD) combination is updated continuously in order to find the appropriate dose combination for each cohort of patients. The probability that the next dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile for the MTD distribution such as to reduce the possibility of over-dosing. Dose escalation, de-escalation or staying at the same doses is determined by searching the MTD combination along rows and columns in a two-drug combination matrix. Simulation studies are conducted to examine the performance of the design under various practical scenarios, and illustrate it with a trial example.