Dose expansion cohorts in Phase I trials.

A rapidly increasing number of Phase I dose-finding studies, and in particular those based on the standard 3+3 design, are being prolonged with the inclusion of dose expansion cohorts (DEC) in order to better characterize the toxicity profiles of experimental agents and to study disease-specific cohorts. These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected. Current protocols do not always specify whether and how the MTD will be updated in light of the new data accumulated from the DEC. In this paper, we propose methods that allow monitoring of safety in the DEC by re-evaluating the MTD in light of additional information. Our working assumption is that, regardless of the design being used for dose escalation, during the DEC we are experimenting in the neighborhood of a target dose with an acceptable rate of toxicity. We refine our initial estimate of the MTD by continuing experimentation in the immediate vicinity of the initial estimate of the MTD. The auxiliary information provided in such an evaluation can include toxicity, pharmacokinetic, efficacy or other endpoints. We consider approaches specifically focused on the aims of DEC that examine efficacy alone or simultaneously with safety and compare the proposed tests via simulations.