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A Bayesian model-free approach to combination therapy phase I trials using censored time-to-toxicity data.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Wheeler, Graham M 
Sweeting, Michael J 
Mander, Adrian P 

Abstract

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.

Description

Keywords

Adaptive designs, Bayesian methods, Clinical trials, Dose escalation, Model-free, Time-to-event

Journal Title

J R Stat Soc Ser C Appl Stat

Conference Name

Journal ISSN

0035-9254
1467-9876

Volume Title

68

Publisher

Oxford University Press (OUP)
Sponsorship
MRC (unknown)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
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).