DrugCombo: an informatics bridge for anticancer drug combination Phase I trial design

Abstract

The promise of combinational drug therapies for cancer is hindered by the high failure rate of Phase I trials, perhaps attributable to the inavailability of an integrated source of toxicity data for cancer drugs to aid clinicians and biostatisticians designing trials. To this end, we developed DrugCombo, a knowledge base that integrates drug toxicity along with other data for single drugs and drug combinations from various sources. We extracted drug toxicity data from drug labels using the Microsoft Research Bidirectional Encoder Representations from Transformers for Biomedical Text Mining (MSR BiomedBERT) and manually from PubMed. DrugCombo is the first such database to contain crucial data, such as maximum tolerable dose (MTD), dose-limiting toxicity (DLT), and dose range, for Phase I clinical trial design as well as pharmacokinetics evidence of drug interaction among cancer drugs. Currently, DrugCombo has integrated 8797 drug interactions from DrugBank; 3995 severe adverse drug events (ADEs) and 95 535 common ADEs from drug labels; 1 816 030 ADEs from United States Food and Drug Administration Adverse Event Reporting System; and MTD and DLTs from 2592 Phase I trials. Using these data, we retrospectively investigated a Phase I trial of axitinib and nivolumab in 12 patients. Exploring the toxicity profile of each drug, we recognized that the initial study design may have overlooked overlap toxicity between them, leading to possibly excessive starting doses and dose ranges of axitinib and nivolumab. DrugCombo provides a comprehensive resource of toxicity data that will assist researchers designing Phase I trials in selecting appropriate starting doses and dose ranges for successful outcomes. Database URL: http://drugcombo.info/.