Phase I Dose-Finding Study of Pazopanib in Hepatocellular Carcinoma: Evaluation of Early Efficacy, Pharmacokinetics, and Pharmacodynamics

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 ¼ 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 þ 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 C max and area under the concentration-time curve (AUC 0-6 ) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K trans were shown at all pazopanib doses

Bevacizumab with Erlotinib as First-line Therapy in Asian Patients with Advanced Hepatocellular Carcinoma: A Multicenter Phase II Study

“…The efficacy end points of this combination, including a response rate of 6%, a PFS-16W of 35.3% and a median PFS of 2.7 months in a cohort of patients enrolled from Asian countries where hepatitis B virus infection is endemic, were comparable to those of sorafenib and other previously reported antiangiogenic therapies [4,9,10,27]. However, the efficacy of the combination demonstrated in this Asian cohort did not meet the preplanned efficacy boundary of 60% PFS-16W, nor was it as effective as initially reported by Thomas et al [17 ]in a USA-based patient cohort.…”

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

“…Hsu et al [110] Thalidomide Perfusion CT 18 High baseline blood flow and blood volume correlates with progression Petralia et al [119] Thalidomide/ radiotherapy DCEMRI [120] CT …”

Clinical Trials in Hepatocellular Carcinoma: An Update

“…Data from clinical trials on a variety of molecular targeted therapies for advanced HCC are shown in table 1[3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56]. …”