Controlled amplification in oncology dose-finding trials

In oncology clinical trials the guiding principle of model-based dose-finding designs for cytotoxic agents is to progress as fast as possible towards, and identify, the dose level most likely to be the MTD. Recent developments with non-cytotoxic agents have broadened the scope of early phase trials to include multiple objectives. The ultimate goal of dose-finding designs in our modern era is to collect the relevant information in the study for final RP2D determination. While some information is collected on dose levels below and in the vicinity of the MTD during the escalation (using conventional tools such as the Continual Reassessment Method for example), designs that include expansion cohorts or backfill patients effectively amplify the information collected on the lower dose levels. This is achieved by allocating patients to dose levels slightly differently during the study in order to take into account the possibility that "less (dose) might be more". The objective of this paper is to study the concept of amplification. Under the heading of controlled amplification we can include dose expansion cohorts and backfill patients among others. We make some general observations by defining these concepts more precisely and study a specific design that exploits the concept of controlled amplification.