Abstract 4394: Utilizing pharmacokinetics and toxicity data in the translational drug interaction knowledgebase to bridge the phase I cancer drug combination studies

Abstract

Abstract Multi-target drug combinations have become essential in overcoming de novo and acquired resistance to cancer therapy. However, pharmacokinetics (PK) and toxicity profiles are the largest valley of death for the combinatory drug therapy development. Although there is rich knowledge in the public domain data sources, it is not yet well integrated or readily available to investigators planning novel clinical trial designs. Incorporating the multitude of datasets available for each drug and drug target would allow for more rationale selection of dose levels and schedules in cancer clinical trial development. In this study, we conducted a feasibility study to demonstrate the utility of an integrated drug interaction knowledge base in the designing cancer drug combination phase 1 clinical trials. Methods: Phase 1 or 1b cancer trials reported in ClincalTrials.gov during 1/1/2018-12/31/2018 were used for target trial selection. The multiple interventions in the study were limited to small molecule cancer drugs and monoclonal antibodies. All the identified drugs/chemicals were normalized via DrugBank. Then, our TDIK(Translational Drug Interaction Knowledgebase) was used to assess whether it has sufficient data to infer drug combination PK or toxicity. The TDIK database has integrated PK and toxicity data from more than 1 million DDI evidence in DrugBank, 69,579 articles indexed in the PubMed, drug labels and our Cancer Drug Fraction of Metabolism Database. Results: 423 cancer drug combination phase I/Ib clinical trials were selected as target trials, in which 496 drug combinations were tested, and they include 487 distinct individual drugs. Among those 487 individual drugs, 221 have PK or toxicity data in TDIK. Among 496 drug combinations, 325 combinations have at least PK drug interaction or drug combination toxicity data. Conclusions: TDIK contains a significant amount of PK and toxicity data on cancer drugs and their combinations. It is a powerful tool in designing drug combination phase I trials. Summary of PK and toxicity knowledge identified by TDIKKnowledge Type# of knowledge found in TDIKCommentsIndividual DrugMetabolism or Transport Pathway84Major pathway, the fractions by each pathway, and inhibition capacityMTD (Maximum tolerated dose)154Other PK parameters (Clearance, maximum concentration, half-life time, etc.14This information is for the drugs that are currently in the study or clinical trial phase.Toxicity information (Adverse drug reactions) in phase 1 or 1b trials19This information is for the drugs that are currently in the study or clinical trial phase.Drug CombinationPK or Pharmacodynamics DDI evidence408Toxicity information(Adverse drug reactions) in drug combination trials247All the information is from phase 1 or 1b clinical trials. Citation Format: Lei Wang, Shijun Zhang, Lai Wei, Dwight H. Owen, Lang Li. Utilizing pharmacokinetics and toxicity data in the translational drug interaction knowledgebase to bridge the phase I cancer drug combination studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4394.