Adaptive dose modification for phase I clinical trials

Most phase I dose‐finding methods in oncology aim to find the maximum‐tolerated dose from a set of prespecified doses. However, in practice, because of a lack of understanding of the true dose–toxicity relationship, it is likely that none of these prespecified doses are equal or reasonably close to the true maximum‐tolerated dose. To handle this issue, we propose an adaptive dose modification (ADM) method that can be coupled with any existing dose‐finding method to adaptively modify the dose, when it is needed, during the course of dose finding. To reflect clinical practice, we divide the toxicity probability into three regions: underdosing, acceptable, and overdosing regions. We adaptively add a new dose whenever the observed data suggest that none of the investigational doses are likely to be located in the acceptable region. The new dose is estimated via a nonparametric dose–toxicity model based on local polynomial regression. The simulation study shows that ADM substantially outperforms the similar existing method. We applied ADM to a phase I cancer trial. Copyright © 2016 John Wiley & Sons, Ltd.