Repository logo
 

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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Knight, Rochelle 
Barnett, Helen 

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.

Description

Keywords

combination study, dose-escalation, interaction, modelling assumption, Bayes Theorem, Clinical Trials, Phase III as Topic, Dose-Response Relationship, Drug, Humans, Logistic Models, Maximum Tolerated Dose, Research Design, Sample Size

Journal Title

Int J Environ Res Public Health

Conference Name

Journal ISSN

1661-7827
1660-4601

Volume Title

18

Publisher

MDPI AG
Sponsorship
NIHR Academy (SRF-2015-08-001)
Medical Research Council (MC_UU_00002/14)