title: Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma.
abstract: Sorafenib is an orally active multikinase inhibitor that targets serine and threonine, and tyrosine kinases that are involved in tumor-cell signal transduction and tumor angiogenesis. This phase I trial was conducted to evaluate the pharmacokinetics (PK), safety, and preliminary efficacy of sorafenib in Japanese patients with hepatocellular carcinoma (HCC) with underlying liver dysfunction. Patients with unresectable HCC, Child-Pugh status A or B, and adequate organ functions were treated. A single dose of sorafenib was administered, followed by a 7-day wash-out period, after which patients received either sorafenib 200 mg (cohort 1) or 400 mg (cohort 2) twice daily. The PK were investigated after a single dose and during steady state. The efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. A total of 27 patients were evaluated for PK, safety, and efficacy. Although both area under the concentration-time curve for 0-12 h and maximal concentration at steady state were slightly lower in Child-Pugh B patients than in Child-Pugh A patients, the difference was not considered to be clinically relevant. Common adverse drug events included elevated lipase, amylase, rash or desquamation, diarrhea, and hand-foot skin reaction. A dose-limiting toxicity of hand-foot skin reaction was observed in one patient (cohort 2). Among the 24 patients evaluable for tumor response, one patient (4%) achieved a partial response, 20 (83%) had stable disease, and three (13%) had progressive disease. Sorafenib demonstrated a favorable tolerability and safety profile in Japanese HCC patients. Moreover, promising preliminary antitumor activity has been observed. Finally, there were no clinically relevant differences in PK between Child-Pugh A and B patients.
authors.affiliation: Division of Hepatobiliary and Pancreatic Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. jfuruse@east.ncc.go.jp
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakachi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakajima
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib