Integrating the escalation and dose expansion studies into a unified Phase I clinical trial.

We focus on Phase I dose finding studies as they are currently undertaken. The design and analysis of these trials have changed over the last years and, in particular, it is now rare for a Phase I study to not include one or more dose-expansion cohorts (DEC). It is common to see DEC involving several hundred patients, building on an initial dose escalation study that may have no >20 to 30 patients. There has been recent focus by researchers on the design of DEC and the analysis of DEC data. It is reasonable to explicitly account for the uncertainty in the estimation of the MTD, the dose upon which the whole of the DEC is currently based. In this paper, we focus on the dose escalation phase prior to the DEC, with the purpose of adapting it to the needs of DEC. Specifically, before beginning the DEC phase, we need to identify those dose levels that will be taken into the DEC. We define a useful concept for this purpose, the co-MTD, and the results support that the estimated MTD and co-MTD contain the true MTD with high probability. We also provide stopping rules for when the data support that the dose escalation can end and the dose expansion can begin. Simulated trials support the use of the proposed approach and provide additional information on how this approach compares with current practice.