Backfilling cohorts in phase I dose-escalation studies. (June 2023)

• Record Type: Journal Article
• Authors: Barnett, Helen; Boix, Oliver; Kontos, Dimitris; Jaki, Thomas
• Is Part Of: Clinical trials. Volume 20:Number 3(2023)
• Page Start: 261
• Page End: 268
• Publication Date: 2023-06
• Subjects: Dose-finding -- dose-escalation -- backfilling -- phase I trials -- model-based -- late-onset toxicity; 615.5072405
• DOI: 10.1177/17407745231160092
• Languages: English
• ISSNs: 1740-7745

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.