Data from Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).</p><p><b>Experimental Design:</b> This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child–Pugh (CP) scores: CP-A (score, 5–6) and CP-B (score, 7–8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with ≤ 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.</p><p><b>Results:</b> In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (<i>C</i><sub>24 h</sub>) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but <i>C</i><sub>24 h</sub> for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit<sup>+</sup> cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (<i>P</i> < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients.</p><p><b>Conclusions:</b> Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A. <i>Clin Cancer Res; 22(6); 1385–94. ©2015 AACR</i>.</p></div>