Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.

PURPOSE: We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. PATIENTS AND METHODS: Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. RESULTS: Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. CONCLUSION: The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.