The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Abstract

Purpose The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase 1 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-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 1328 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 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 since baseline liver tests did not.

Reverse Translation of US Food and Drug Administration Reviews of Oncology New Molecular Entities Approved in 2011–2017: Lessons Learned for Anticancer Drug Development

“…This review also indicated that organ impairment evaluations represent one of the most common reasons for clinical pharmacology-related PMRs/PMCs, particularly in the setting of hepatic impairment. 8,44 This may reflect the fact that enrollment in organ impairment studies in oncology patients is challenging and may take several years to complete, particularly when enrolling patients with severe impairment. Population PK modeling was used commonly in lieu of dedicated studies to evaluate the effect of at least one category of renal or hepatic impairment, most frequently for monoclonal antibodies.…”

Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Dysfunction

“…Alisertib is cytotoxic, and so the study was conducted in cancer patients rather than healthy subjects. Thus, the categorization of hepatic impairment was based on the National Cancer Institute Organ Dysfunction Working Group criteria, which are widely used in hepatic impairment studies of antineoplastic agents in cancer patients . A single‐dose study was designed to address the primary objectives based on prior knowledge of alisertib exhibiting linear PK without time dependence.…”

“…Thus, the categorization of hepatic impairment was based on the National Cancer Institute Organ Dysfunction Working Group criteria, which are widely used in hepatic impairment studies of antineoplastic agents in cancer patients. 16,[21][22][23][24][25][26] A single-dose study was designed to address the primary objectives based on prior knowledge of alisertib exhibiting linear PK without time dependence. However, because the study was conducted in patients with advanced malignancies without treatment options, a multiple-dose phase (7 days' treatment in 21-day cycles) was also part of the protocol to allow potential benefit to patients.…”

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors

“…For the multivariate approach, individual pexidartinib exposures were predicted from the individual post hoc PK parameters and then summarized and compared among subgroups of patients who had normal renal function (CRCL ≥90 mL/min), mild (CRCL 60-89 mL/min) or moderate (CRCL 30-59 mL/min) renal impairment, 8 or subgroups of patients with normal hepatic function or mild hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group classification. 9…”