BARD: A seamless two-stage dose optimization design integrating backfill and adaptive randomization

Date:	August 22, 2025
PMID:	PMC12240483
Category:	N/A
Authors:	Yixuan Zhao, Rachael Liu, Jianchang Lin, Ying Yuan
Abstract:	40626646

One common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose, followed by a randomization stage where patients are assigned to two or more doses to further assess and compare their risk-benefit profiles to identify the optimal dose. A limitation of this approach is its requirement for a relatively large sample size. To address this challenge, we propose a seamless two-stage design, BARD (Backfill and Adaptive Randomization for Dose Optimization), which incorporates two key features to reduce sample size and shorten trial duration. The first feature is the integration of backfilling into the stage 1 dose escalation, enhancing patient enrollment and data generation without prolonging the trial. The second feature involves seamlessly combining patients treated in stage 1 with those in stage 2, enabled by covariate-adaptive randomization, to inform the optimal dose and thereby reduce the sample size. Our simulation study demonstrates that BARD reduces the sample size, improves the accuracy of identifying the optimal dose, and maintains covariate balance in randomization, allowing for unbiased comparisons between doses. BARD designs offer an efficient solution to meet the dose optimization requirements set by Project Optimus, with software freely available at www.trialdesign.org.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center