Phase I study of Pazopanib (PAZ) in Hepatocellular Carcinoma (HCC): evaluation of clinical activity, Pharmacokinetics (PK), and Dynamic Contrast Enhanced MRI (DCE-MRI)

Abstract

Background: HCC is a highly vascular tumor with increased levels of VEGF and VEGFR. PAZ is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, & c-Kit. A correlation between a trough plasma PAZ concentration (C24) of 15 mg/ml and markers of pharmacodynamic activity has been demonstrated in previous studies. DCE-MRI is a noninvasive imaging technique that can provide indices related to blood flow & vascular permeability. A Phase I study was conducted to determine the MTD as well as evaluate safety, PK, DCE-MRI changes, & clinical activity of PAZ in pts with locally unresectable or advanced HCC. Methods: Eligibility criteria included HCC with at least 1 target lesion, recovery from prior therapy, PS 0 or 1, Child-Pugh A, & adequate organ function. PAZ was escalated from 200 to 800 mg QD. DCE-MRI was performed to determine Ktrans (contrast transfer coefficient) & IAUC60 (initial area under the contrast enhancement curve), at baseline & Day 22. PAZ PK, including C24, was determined on Day 15 of Cycle 1.

Median C24 was >15 mg/mL at all doses evaluated. Median changes in Ktrans & IAUC were negative in all dose groups with the greatest median decline at 800 mg. Decreases in IAUC60 were correlated with Cmax and trough concentration. At the MTD of 600 mg QD, median decline from baseline in imaging markers was ~40%; 67% of pts achieved C24 15 ug/mL. Of 10 pts who received 600 mg QD for the largest number of days on study, 7 demonstrated clinical benefit (6 with SD 4 mo & 1 with confirmed PR). The 2 pts with confirmed PRs (1 each at 600 mg & 800 mg QD) both achieved C24 >25 ug/mL. 1 pt with PR & imaging data achieved >60% declines in Ktrans & IAUC relative to baseline. Conclusions: In pts with HCC, the recommended Phase II dose for PAZ of 600 mg QD achieved target trough concentrations associated with clinical benefit & demonstrated meaningful changes in imaging markers.