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.

Figure 1

A 48‐year‐old man with multiple tumors of hepatocellular carcinoma (HCC) after hepatectomy, percutaneous ethanol injection, and transcatheter arterial embolization. (a) Hypervascular HCC lesion, 1 cm in diameter, was revealed at the early phase of dynamic computed tomography (CT) before administration of sorafenib at the anterior superior segment of the liver (arrow). (b) The vascularity of this tumor disappeared 1 month after the administration of sorafenib. (c) The tumor was reduced 3 months after the administration of sorafenib. (d) Another hypervascular HCC lesion, 1 cm in diameter, was revealed at the early phase of dynamic CT before administration of sorafenib in the left lobe of the liver (arrow). (e) The vascularity of this tumor disappeared 8 months after the administration of sorafenib. (f) The tumor almost completely disappeared 10 months after the administration of sorafenib.

Figure 2

Time to progression (TTP) in all 27 patients treated with sorafenib. The median TTP was 4.9 months, and the 6‐month survival rate was 46.2%. Overall survival (OS) in the 27 patients treated with sorafenib. The median OS period was 15.6 months, and the 1‐year survival rate was 59.3%.