COMIC: A Bayesian Dose Optimization Design for Drug Combination in Multiple Indications With Application to CAR-T Therapies

Date:	May 2025
PMID:	40386962
Category:	N/A
Authors:	Kai Chen, Kentaro Takeda, Ying Yuan
Abstract:

Project Optimus, initiated by the US Food and Drug Administration (FDA), seeks to shift the focus of dose finding and selection from the maximum tolerated dose to the optimal dose that offers the most favorable risk-benefit balance. However, applying this paradigm shift to drug combination trials presents challenges, particularly due to limited sample sizes and a large two-dimensional dose exploration space. These challenges are amplified when trials involve multiple indications. To address this, we developed a two-stage Bayesian dose optimization design, called COMIC (Combination Optimization in Multiple IndiCations), to efficiently identify Optimal Biological Dose Combinations (OBDC) for multiple indications. The COMIC design follows a two-stage strategy: First, optimizing the dose for one indication based on a utility function that measures the risk-benefit tradeoff, and then using that data to inform and accelerate dose optimization for additional indications. This approach significantly reduces the required sample size. Additionally, we incorporate a pharmacodynamic endpoint (e.g., receptor occupancy) to prioritize which component of the combination should be escalated, further enhancing the efficiency of dose optimization. Simulation studies demonstrate the strong performance and robustness of the COMIC design across various scenarios. We illustrate the method using a CAR-T therapy trial.

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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