Backfilling cohorts in phase I dose-escalation studies.

Area of Science:

• Clinical Trials
• Pharmacology
• Biostatistics

Background:

• Backfilling assigns additional patients to safe doses in Phase I trials.
• This practice gathers more data on drug safety, pharmacokinetics, and activity.
• It aids in reliably estimating the maximum tolerated dose (MTD) and determining the recommended Phase II dose.

Purpose of the Study:

• To investigate the impact of backfilling on MTD estimation in Phase I trials.
• To assess how backfilling affects the overall duration of Phase I studies.
• To evaluate scenarios with single-cycle follow-up and delayed toxicities.

Main Methods:

• Simulated Phase I dose-escalation trials incorporating backfilling.
• Analysis of MTD estimation accuracy under various conditions.
• Assessment of trial duration with and without backfilling.

Main Results:

• Backfilling increased the percentage of correct MTD selections by up to 9% across scenarios.
• Each additional backfilling patient reduced trial duration by approximately half a week for a 6-week cycle.
• The impact on accuracy was more pronounced with a one-cycle toxicity assessment period.

Conclusions:

• Backfilling significantly enhances MTD estimation accuracy in Phase I studies.
• A notable reduction in trial duration is achieved through backfilling.
• Increased accuracy and reduced duration come with the trade-off of a larger sample size.