ABSTRACT
Drug combination therapy has become the mainstream approach to cancer treatment. It provides the means by which treatment efficacy is improved and the resistance to treatment that impedes cancer monotherapy is overcome. The objectives of using drug combination are to induce a synergistic treatment effect, increase the joint dose intensity with nonoverlapping toxicities, and target various tumor cell susceptibilities and disease pathways. A search on PubMed with the keyword “drug combination” identified more than 88,000 publications from 2010 to 2015. However, despite the enormous importance and apparent popularity of combination therapies, in terms of the designs used in actual trials of drug combinations, the current status is far from desirable. Riviere et al. [1] reviewed 162 trials published between 2011 and 2013 and found that 88% of the trials used the conventional 3 + 3 design, which has been widely criticized for its poor operating characteristics, even when used for single-agent trials. They found only one trial that used a new design for combination trials, despite the availability of more than a dozen novel combination trial designs in the (mainly statistical) literature. As we describe herein, the design of drug combination trials is more complicated and challenging than that of single-agent trials. The goal of this chapter is to clarify some challenges (Section 6.1) and misconceptions on designing combination trials (Section 6.2) and provide practical guidance and designs to practitioners for conducting drug combination trials (Section 6.3).
