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Abstract:
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Most phase I dose-finding methods in oncology aim to find the maximum-tolerated dose (MTD) from a set of prespecified doses. However, in practice, due to a lack of understanding of the true dose-toxicity relationship, it is likely that none of these prespecified doses is equal or reasonably close to the true MTD. To handle this issue, we propose an adaptive dose modification (ADM) method that can be coupled with any existing dose-finding method to adaptively add a 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 dose whenever the observed data suggest that none of the investigational doses is likely to be located in the acceptable region. The added dose is estimated via a nonparametric dose-toxicity model based on local polynomial regression. The simulation study shows that ADM outperforms the similar existing method, with more precise added doses. We applied ADM to a phase I cancer trial.
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