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Dose finding studies for therapies with late-onset toxicities: A comparison study of designs.

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Boix, Oliver 
Kontos, Dimitris 


An objective of phase I dose-finding trials is to find the maximum tolerated dose; the dose with a particular risk of toxicity. Frequently, this risk is assessed across the first cycle of therapy. However, in oncology, a course of treatment frequently consists of multiple cycles of therapy. In many cases, the overall risk of toxicity for a given treatment is not fully encapsulated by observations from the first cycle, and hence it is advantageous to include toxicity outcomes from later cycles in phase I trials. Extending the follow up period in a trial naturally extends the total length of the trial which is undesirable. We present a comparison of eight methods that incorporate late onset toxicities while not extensively extending the trial length. We conduct simulation studies over a number of scenarios and in two settings; the first setting with minimal stopping rules and the second setting with a full set of standard stopping rules expected in such a dose finding study. We find that the model-based approaches in general outperform the model-assisted approaches, with an interval censored approach and a modified version of the time-to-event continual reassessment method giving the most promising overall performance in terms of correct selections and trial length. Further recommendations are made for the implementation of such methods.



dose-finding, late-onset toxicities, model-assisted, model-based, phase I trials, Humans, Dose-Response Relationship, Drug, Maximum Tolerated Dose, Longitudinal Studies, Computer Simulation, Research Design, Bayes Theorem

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Stat Med

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NIHR Academy (SRF-2015-08-001)
Medical Research Council (MC_UU_00002/14)
National Institute for Health and Care Research (IS-BRC-1215-20014)