Using an Interaction Parameter in Model-Based Phase I Trials for Combination Treatments? A Simulation Study

Pavel Mozgunov, Rochelle Knight, Helen Barnett and Thomas Jaki
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Pavel Mozgunov: Department of Mathematics and Statistics, Lancaster University, Lancaster LA1 4YF, UK
Rochelle Knight: Department of Mathematics and Statistics, Lancaster University, Lancaster LA1 4YF, UK
Helen Barnett: Department of Mathematics and Statistics, Lancaster University, Lancaster LA1 4YF, UK
Thomas Jaki: Department of Mathematics and Statistics, Lancaster University, Lancaster LA1 4YF, UK

IJERPH, 2021, vol. 18, issue 1, 1-19

Abstract: There is growing interest in Phase I dose-finding studies studying several doses of more than one agent simultaneously. A number of combination dose-finding designs were recently proposed to guide escalation/de-escalation decisions during the trials. The majority of these proposals are model-based: a parametric combination-toxicity relationship is fitted as data accumulates. Various parameter shapes were considered but the unifying theme for many of these is that typically between 4 and 6 parameters are to be estimated. While more parameters allow for more flexible modelling of the combination-toxicity relationship, this is a challenging estimation problem given the typically small sample size in Phase I trials of between 20 and 60 patients. These concerns gave raise to an ongoing debate whether including more parameters into combination-toxicity model leads to more accurate combination selection. In this work, we extensively study two variants of a 4-parameter logistic model with reduced number of parameters to investigate the effect of modelling assumptions. A framework to calibrate the prior distributions for a given parametric model is proposed to allow for fair comparisons. Via a comprehensive simulation study, we have found that the inclusion of the interaction parameter between two compounds does not provide any benefit in terms of the accuracy of selection, on average, but is found to result in fewer patients allocated to the target combination during the trial.

Keywords: dose-escalation; combination study; modelling assumption; interaction (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2021
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