A Phase I/II Clinical Trial Design for Drug Combinations

• Activity Number: 554
• Type: Topic Contributed
• Date/Time: Wednesday, August 1, 2012 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Xuelin Huang*+ and Sangbum Choi
• Companies: MD Anderson Cancer Center and MD Anderson Cancer Center
• Keywords: Clinical trial design ; Dose selection ; Efficacy ; Synergism ; Toxicity

Abstract

The use of multiple drugs in a single clinical trial has become common, particularly in the treatment of cancer. A traditional phase I trial design for a single drug is to evaluate its dose-toxicity curve and select the highest tolerable dose level. The underlying assumption is that, for a single agent, higher doses give higher toxicity and also higher efficacy. However, the extension of this assumption to drug combinations has a problem. That is, on a two-dimensional plane, not all combination doses can have a clear order about which one is "higher". In such a case, we emphasize that the dose selection for combination therapies should not be based on toxicity, rather it should be based on efficacy. The ratio of the doses of two drugs that yield synergism in efficacy may be quite different from that for toxicity. With this in mind, in place of the traditional separate phase I and II trials, we propose using a parallel phase I/II clinical trial to evaluate simultaneously the safety and efficacy of combination dose levels, and select the optimal combination dose based on efficacy, or a well-defined utility function combing both efficacy and toxicity.