A phase I study of pazopanib in patients with advanced hepatocellular carcinoma

Abstract

3561 Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) have a poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors including VEGF and VEGFR. Pazopanib (GW786034) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit. A Phase I study was conducted to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics and efficacy of pazopanib in patients with locally unresectable and/or advanced HCC. Methods: Eligibility criteria included unresectable and/or metastatic HCC with at least 1 target lesion, recovery from prior systemic regimens, ECOG PS 0 or 1, Child-Pugh A, and adequate organ function. Doses of pazopanib were escalated from 200 mg once daily (QD) to 800 mg QD in a 3 + 3 design. DCE- MRI was performed to assess changes in tumor permeability. Results: 27 Asian pts have been enrolled at QD doses of 200 (4 pts), 400 (10), 600 (8), 800 (5): median (range) age = 61 (38–76); M/F = 85%/15%; ECOG 0/1 = 59%/41%; 81% with metastatic disease; 67% with Stage IV; 22% with prior systemic therapy, 26% with prior TACE. Most common AEs were: diarrhea (59%; 4% Gr 3); hypertension (44%; 26% Gr 3), cough (19%); fatigue (19%; 4% Gr 3); and hair depigmentation (15%). Hepatobiliary lab abnormalities were: AST elevation (63%; 15% Gr 3), hyperbilirubinemia (63%; 4% Gr 3), ALT elevation (41%; 7% Gr 3), and Alk phos (37%; 4% Gr 3). DLTs were Gr 3 malaise (1 pt) and Gr 3 AST/ALT elevation (1 pt) at 800 mg. MTD was determined to be 600 mg QD. Median (range) days on study was 85 (4–663) overall; 106 days (4–274) at the MTD. Best response was PR in 2 pts (7%; 1 at 800mg, 1 at 600 mg) and SD > 4 mos in 11 pts (41%). Median TTP at the MTD was 137.5 days (4–280 days). Median % change in tumor permeability (Ktrans) following 3 weeks of pazopanib administration at the MTD (5 pts) was 45%. Predose and maximum plasma pazopanib concentrations at 800 mg QD were similar to values observed previously at the same dose. Conclusions: Pazopanib has a manageable safety profile in HCC at the MTD of 600mg QD. Preliminary evidence of antitumor activity was observed. Changes in tumor DCE-MRI parameters were seen following repeated dose pazopanib administration. [Table: see text]