Principled Drug-Drug Interaction Terms for Bayesian Logistic Regression Models of Drug Safety in Oncology Phase I Combination Trials

Abstract: In Oncology, trials evaluating drug combinations are becoming more common. While combination therapies bring the potential for greater efficacy, they also create unique challenges for ensuring drug safety. In Phase-I dose escalation trials of drug combinations, model-based approaches enable efficient use of information gathered, but the models need to account for trial complexities: appropriate modeling of interactions becomes increasingly important with growing numbers of drugs being tested simultaneously in a given trial. In principle, we can use data from multiple arms testing varying combinations to jointly estimate toxicity of the drug combinations. However, such efforts have highlighted limitations when modelling drug-drug interactions in the Bayesian Logistic Regression Model (BLRM) framework used to ensure patient safety. Previous models either do not account for non-monotonicity due to antagonistic toxicity, or exhibit the fundamental flaw of exponentially overpowering the contributions of the individual drugs in the dose-response. This specifically leads to issues when drug combinations exhibit antagonistic toxicity, in which case the toxicity probability gets vanishingly small as doses get very large. We put forward additional constraints inspired by Paracelsus' intuition of "the dose makes the poison" which avoid this flaw and present an improved interaction model which is compatible with these constraints. We create instructive data scenarios that showcase the improved behavior of this more constrained drug-drug interaction model in terms of preventing further dosing at overly toxic dose combinations and more sensible dose-finding under antagonistic drug toxicity. This model is now available in the open-source OncoBayes2 R package that implements the BLRM framework for an arbitrary number of drugs and trial arms.