A Bayesian model-free approach to combination therapy phase I trials using censored time-to-toxicity data.
Wheeler, Graham M
Sweeting, Michael J
Mander, Adrian P
J R Stat Soc Ser C Appl Stat
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Wheeler, G. M., Sweeting, M. J., & Mander, A. P. (2019). A Bayesian model-free approach to combination therapy phase I trials using censored time-to-toxicity data.. J R Stat Soc Ser C Appl Stat, 68 (2), 309-329. https://doi.org/10.1111/rssc.12323
The product of independent beta probabilities escalation (PIPE) design for dual-agent phase I dose-escalation trials is a Bayesian model-free approach for identifying multiple maximum tolerated dose combinations of novel combination therapies. Despite only being published in 2015, the PIPE design has been implemented in at least two oncology trials. However, these trials require patients to have completed follow-up before clinicians can make dose-escalation decisions. For trials of radiotherapy or advanced therapeutics, this may lead to impractically long trial durations due to late-onset treatment-related toxicities. In this paper, we extend the PIPE design to use censored time-to-event (TITE) toxicity outcomes for making dose escalation decisions. We show via comprehensive simulation studies and sensitivity analyses that trial duration can be reduced by up to 35%, particularly when recruitment is faster than expected, without compromising on other operating characteristics.
A. P. Mander is supported by the UK Medical Research Council (grant number G0800860). Additional support for this project for work done at the University of Cambridge came from the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation (RG/13/13/30194) and the UK National Institute for Health Research (Cambridge Biomedical Research Centre).
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
External DOI: https://doi.org/10.1111/rssc.12323
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288021
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/