The effect of hepatic impairment on outcomes in phase I clinical trials in cancer subjects

NCI Organ Dysfunction Working Group

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsoredHDCTand 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.

Original languageEnglish (US)
Pages (from-to)5472-5479
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2016

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Clinical Trials, Phase I
Liver
Neoplasms
Chemical and Drug Induced Liver Injury
Program Evaluation
Transaminases
Alanine Transaminase
Bilirubin
Antineoplastic Agents
Alkaline Phosphatase
Disease Progression
Appointments and Schedules
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The effect of hepatic impairment on outcomes in phase I clinical trials in cancer subjects. / NCI Organ Dysfunction Working Group.

In: Clinical Cancer Research, Vol. 22, No. 22, 15.11.2016, p. 5472-5479.

Research output: Contribution to journalArticle

NCI Organ Dysfunction Working Group. / The effect of hepatic impairment on outcomes in phase I clinical trials in cancer subjects. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 22. pp. 5472-5479.
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abstract = "Purpose: 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. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsoredHDCTand 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.",
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