Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

• Authors: Stephen I Shibata, City of Hope, Duarte; Vincent Chung, City of Hope, Duarte; Timothy Synold, City of Hope, Duarte; Jeffrey Longmate, City of Hope, Duarte; A Benjamin Suttle, GlaxoSmithKline; Lone H Ottesen, GlaxoSmithKline; Heinz-Josef Lenz, University of Southern California; Shivaani Kummar, National Cancer Institute, Bethesda; R. Harvey, Emory University; Anne Hamilton, Royal Prince Alfred, Sydney; Bert O'Neil, UNC Lineberger, Chapel Hill; John Sarantopoulos, Institute for Drug Development CTRC, San Antonio; Patricia LoRusso, Wayne State University; Michelle A Rudek, Johns Hopkins; Afshin Dowlati, Case Western Reserve; Daniel Mulkerin, University of Wisconsin; Chandra P. Belani, Penn State, Hershey; Leena Gandhi, Dana-Farber, Boston; Cecilia Lau, City of Hope, Duarte; S. Percy Ivy, NCI CTEP, Bethesda
• Journal Title: Clinical Cancer Research
• Volume: Volume 19, Number 13
• Publisher: American Association for Cancer Research | 2013-07-01, Pages 3631-3639
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1078-0432.CCR-12-3214
• Subjects: Health Sciences, Oncology; Health Sciences, Public Health; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; ORAL PAZOPANIB; INHIBITOR; TRIAL

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.