title: The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects.
abstract: OBJECTIVE
  The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents.
  
  
  METHODS
  Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups.
  
  
  RESULTS
  There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT.
  
  
  CONCLUSIONS
  The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472-9. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. mansfield.aaron@mayo.edu.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Mansfield
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Theradex, Princeton, New Jersey.
authors.forename: Diana
authors.initials: D
authors.lastname: Vulih
authors.affiliation: Clinical Trials Monitoring Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Smith
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Pamela Jo
authors.initials: PJ
authors.lastname: Harris
authors.affiliation: Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
mesh_terms: D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001663:Bilirubin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D008111:Liver Function Tests / Q000379:methods; D008297:Male; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin