Backfilling Cohorts in Phase I Dose-Escalation Studies

TL;DR

This paper investigates how backfilling in phase I dose-escalation trials affects the accuracy of MTD estimation and study duration, highlighting benefits and trade-offs in different scenarios.

Contribution

It provides a systematic analysis of backfilling's impact on trial outcomes, including effects on MTD estimation accuracy and trial duration under various conditions.

Findings

Increased correct MTD selection rate with backfilling

Reduced trial duration when using backfilling

More patients are required when employing backfilling

Abstract

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 (MTD) is reliably estimated and give additional information in order to determine the recommended phase II dose (RP2D). In this paper, we study the effect of employing backfilling in a phase I trial on the estimation of the MTD 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. We find that, over a range of scenarios, there is an increase in the proportion of correct selections and a notable reduction in the trial duration at the cost of more patients required in the study.