An adaptive design for the identification of the optimal dose using joint modeling of continuous repeated biomarker measurements and time-to-toxicity in phase I/II clinical trials in oncology
Restricted accessResearch articleFirst published online February, 2020
An adaptive design for the identification of the optimal dose using joint modeling of continuous repeated biomarker measurements and time-to-toxicity in phase I/II clinical trials in oncology
We present a new adaptive dose-finding method, based on a joint modeling of longitudinal continuous biomarker activity measurements and time to first dose limiting toxicity, with a shared random effect. Estimation relies on likelihood that does not require approximation, an important property in the context of small sample sizes, typical of phase I/II trials. We address the important case of missing at random data that stem from unacceptable toxicity, lack of activity and rapid deterioration of phase I patients. The objective is to determine the lowest dose within a range of highly active doses, under the constraint of not exceeding the maximum tolerated dose. The maximum tolerated dose is associated to some cumulative risk of dose limiting toxicity over a predefined number of treatment cycles. Operating characteristics are explored via simulations in various scenarios.
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