Backfilling cohorts in phase I dose-escalation studies

Barnett, Helen and Boix, Oliver and Kontos, Dimitris and Jaki, Thomas (2023) Backfilling cohorts in phase I dose-escalation studies. Clinical Trials, 20 (3). pp. 261-268. ISSN 1740-7745

Text (Backfilling_paper_SAGE_template_R1_clean)
Backfilling_paper_SAGE_template_R1_clean.pdf - Accepted Version
Available under License Creative Commons Attribution.
Download (352kB)

Abstract

Background: The use of ‘backfilling’, assigning additional patients to doses deemed safe, in phase I dose-escalation studies has been used in practice to collect additional information on the safety profile, pharmacokinetics and activity of a drug. These additional patients help ensure that the maximum tolerated dose is reliably estimated and give additional information to determine the recommended phase II dose. Methods: In this article, we study the effect of employing backfilling in a phase I trial on the estimation of the maximum tolerated dose and the duration of the study. We consider the situation where only one cycle of follow-up is used for escalation as well as the case where there may be delayed onset toxicities. Results: We find that, over a range of scenarios, the use of backfilling gives an increase in the percentage of correct selections by up to 9%. On average, for a treatment with a cycle length of 6 weeks, each additional backfilling patient reduces the trial duration by half a week. Conclusions: Backfilling in phase I dose-escalation studies can substantially increase the accuracy of estimation of the maximum tolerated dose, with a larger impact in the setting with a dose-limiting toxicity event assessment period of only one cycle. This increased accuracy and reduction in the trial duration are at the cost of increased sample size.