Designing trials for drug combinations

This chapter proposes pragmatic considerations for designing early phase clinical trials as well as the molecular and pharmacological audit trail (MoPhAT) framework, which includes the steps needed to successfully develop molecular targeted combination regimens. Key definitions of biomarkers and how they should be developed, validated, and incorporated in combination clinical trials are outlined. Novel trial designs to develop early phase trials involving rational combinations of antitumor agents are also discussed. Clinical trial designs for combination regimens should ideally include toxicity monitoring strategies, mechanism-of-action combinatorial pharmacodynamic studies, detailed pharmacokinetic profiling, and exploratory studies to assess putative predictive biomarkers of response and resistance of the combination. Biomarker-based studies enable the clinical testing of rational combinatorial regimens of investigational agents using an evidence-based and hypothesis-driven approach. The MoPhAT approach may fully exploit our improved understanding of cancer biology and the latest technological advances, leading to accelerated drug development and improved outcomes for patients.