Design Issues in Dose-Finding Phase I Trials for Combinations of Two Agents

Combination therapy of two antitumor agents may provide treatment additivity or synergy. Phase I trials for combination therapy search for the maximum tolerated dose (MTD) for combined agents. The conventional approach is to preselect an escalation path, usually increasing the dose of one agent and then another, and to use the standard 3 + 3 design. However, this procedure may miss the optimum dose combination, prolong the time it takes, and increase the number of patients necessary to reach the MTD. In this study, we present strategies for a comprehensive search for MTD for a two-agent combination therapy. We evaluate algorithms based on two-stage and three-stage design as well as variations in cohort size. A two-dimensional isotonic estimation method for toxicity rate is provided. We use simulation methods to compare 2 + 1 + 3 vs. 3 + 3 cohort sizes. We conclude that the comprehensive search proposed in our study can be more practical and efficient in identifying the MTD in combination-therapy of two agents.