Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma
Mené sur 20 patients atteints d'un carcinome hépatocellulaire de stade avancé, cet essai de phase I évalue la dose maximale tolérée et l'activité clinique du lenvatinib
Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: This multicenter, open-label, phase 1, dose-escalation study included patients aged 20-80 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 (QD) 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. Results: In total, twenty patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg QD 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 (C24h) for 12 mg QD was higher in patients with HCC versus patients with other solid tumors shown in previous phase 1 study, but C24h for 25 mg QD lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL-10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. Conclusion: Lenvatinib (12 mg QD) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase 2 studies in patients with HCC and CP-A.