LAUSR

We consider the design of phase II trials evaluating combinations of experimental therapies. In the modern era, many immunotherapy and targeted therapy regimens are being developed as combination regimens, including combinations consisting only of experimental agents. In some clinical/drug development scenarios, it may be difficult to isolate the effect of the individual agents making up a combination of this type, which makes the evaluation of the combination challenging. One such scenario arises when none of the agents making up the experimental combination have demonstrated single-agent activity in the clinical setting of interest. One solution to this problem is to employ a randomized comparative trial in which the combination of interest is compared with one or both of its component agents, but because all arms in such a trial would be experimental, some modifications to more traditional randomized comparative phase II trials must be made. In this manuscript, we present sensible modifications to randomized phase II trial designs that can be employed in two common drug development scenarios of this type and provide a detailed discussion of the practical aspects of designing these trials. We also include two worked examples to further illustrate how to design such a trial.