Phase I dose-finding study of pazopanib in hepatocellular carcinoma: Evaluation of early efficacy, pharmacokinetics, and pharmacodynamics
Journal
Clinical Cancer Research
Journal Volume
17
Journal Issue
21
Pages
6914-6923
Date Issued
2011
Author(s)
Abstract
Background: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean Cmax and area under the concentration-time curve (AUC0-6) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and Ktrans were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C24 and Cmax values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. ?2011 AACR.
SDGs
Other Subjects
gsk 1071306; gsk 1268992; gsk 1268997; pazopanib; unclassified drug; abdominal distension; abdominal pain; adult; advanced cancer; alanine aminotransferase blood level; alopecia; anorexia; antineoplastic activity; area under the curve; article; Asian; aspartate aminotransferase blood level; clinical article; contrast enhancement; controlled study; coughing; depigmentation; diarrhea; dizziness; drug activity; drug blood level; drug dose escalation; drug efficacy; drug safety; dynamic contrast enhanced nuclear magnetic resonance imaging; fatigue; female; gastrointestinal hemorrhage; human; hyperbilirubinemia; hypercholesterolemia; hypertension; hypoglycemia; hypokalemia; hyponatremia; hypopigmentation; leukopenia; liver cell carcinoma; liver function test; malaise; male; maximum plasma concentration; maximum tolerated dose; multiple cycle treatment; muscle spasm; nausea; nuclear magnetic resonance imaging; pharmacodynamics; phase 1 clinical trial; priority journal; side effect; treatment response; tumor vascularization; upper respiratory tract infection; weight reduction
Publisher
American Association for Cancer Research Inc.
Type
journal article