SDF-Bayes: Cautious Optimism in Safe Dose-Finding Clinical Trials with Drug Combinations and Heterogeneous Patient Groups
Hyun-Suk Lee, Cong Shen, William Zame, Jang-Won Lee, Mihaela van der Schaar
Abstract
Phase I clinical trials are designed to test the safety (non-toxicity) of drugs and find the maximum tolerated dose (MTD). This task becomes significantly more challenging when multiple-drug dose-combinations (DC) are involved, due to the inherent conflict between the exponentially increasing DC candidates and the limited patient budget. This paper proposes a novel Bayesian design, SDF-Bayes, for finding the MTD for drug combinations in the presence of safety constraints. Rather than the conventional principle of escalating or de-escalating the current dose of one drug (perhaps alternating between drugs), SDF-Bayes proceeds by cautious optimism: it chooses the next DC that, on the basis of current information, is most likely to be the MTD (optimism), subject to the constraint that it only chooses DCs that have a high probability of being safe (caution). We also propose an extension, SDF-Bayes-AR, that accounts for patient heterogeneity and enables heterogeneous patient recruitment. Extensive experiments based on both synthetic and real-world datasets demonstrate the advantages of SDF-Bayes over state of the art DC trial designs in terms of accuracy and safety.
BibTeX
@InProceedings{pmlr-v130-lee21c,
title = { SDF-Bayes: Cautious Optimism in Safe Dose-Finding Clinical Trials with Drug Combinations and Heterogeneous Patient Groups },
author = {Lee, Hyun-Suk and Shen, Cong and Zame, William and Lee, Jang-Won and van der Schaar, Mihaela},
booktitle = {Proceedings of The 24th International Conference on Artificial Intelligence and Statistics},
pages = {2980--2988},
year = {2021},
editor = {Banerjee, Arindam and Fukumizu, Kenji},
volume = {130},
series = {Proceedings of Machine Learning Research},
month = {13--15 Apr},
publisher = {PMLR},
pdf = {http://proceedings.mlr.press/v130/lee21c/lee21c.pdf},
url = {https://proceedings.mlr.press/v130/lee21c.html},
abstract = { Phase I clinical trials are designed to test the safety (non-toxicity) of drugs and find the maximum tolerated dose (MTD). This task becomes significantly more challenging when multiple-drug dose-combinations (DC) are involved, due to the inherent conflict between the exponentially increasing DC candidates and the limited patient budget. This paper proposes a novel Bayesian design, SDF-Bayes, for finding the MTD for drug combinations in the presence of safety constraints. Rather than the conventional principle of escalating or de-escalating the current dose of one drug (perhaps alternating between drugs), SDF-Bayes proceeds by cautious optimism: it chooses the next DC that, on the basis of current information, is most likely to be the MTD (optimism), subject to the constraint that it only chooses DCs that have a high probability of being safe (caution). We also propose an extension, SDF-Bayes-AR, that accounts for patient heterogeneity and enables heterogeneous patient recruitment. Extensive experiments based on both synthetic and real-world datasets demonstrate the advantages of SDF-Bayes over state of the art DC trial designs in terms of accuracy and safety. }
}