Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.
OBJECTIVE
To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).


METHODS
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.


RESULTS
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 (C24 h) 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 C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL10, 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.


CONCLUSIONS
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.
National Cancer Center Hospital East, Chiba, Japan. masikeda@east.ncc.go.jp.
Masafumi
M
Ikeda
National Cancer Center Hospital, Tokyo, Japan.
Takuji
T
Okusaka
National Cancer Center Hospital East, Chiba, Japan.
Shuichi
S
Mitsunaga
National Cancer Center Hospital, Tokyo, Japan.
Hideki
H
Ueno
Clinical Development, Eisai Co., Ltd., Tokyo, Japan.
Toshiyuki
T
Tamai
Clinical Development, Eisai Co., Ltd., Tokyo, Japan.
Takuya
T
Suzuki
Clinical Pharmacology, Eisai Co., Ltd., Tokyo, Japan.
Seiichi
S
Hayato
Biomarkers and Personalized Medicine Core Function Unit, Eisai Co., Ltd., Tsukuba, Japan.
Tadashi
T
Kadowaki
Shunan Memorial Hospital, Yamaguchi, Japan.
Kiwamu
K
Okita
Toranomon Hospital, Tokyo, Japan.
Hiromitsu
H
Kumada
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib