Phase i study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: A national cancer institute organ dysfunction working group study

Stephen I. Shibata, Vincent Chung, Timothy W. Synold, Jeffrey A. Longmate, A. Benjamin Suttle, Lone H. Ottesen, Heinz Josef Lenz, Shivaani Kummar, R. Donald Harvey, Anne L. Hamilton, Bert H. O'Neil, John Sarantopoulos, Patricia LoRusso, Michelle A. Rudek, Afshin Dowlati, Daniel L. Mulkerin, Chandra P. Belani Leena Gandhi, S. Cecilia Lau, S. Percy Ivy, Edward M. Newman

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 33 design was used. Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24) ] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.

Original languageEnglish (US)
Pages (from-to)3631-3639
Number of pages9
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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