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.

Abstract

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.

• Authors: Masafumi Ikeda, Shuichiro Shiina, Kohei Nakachi, Shuichi Mitsunaga, Satoshi Shimizu, Yasushi Kojima, Hideki Ueno, Chigusa Morizane, Shunsuke Kondo, Yasunari Sakamoto, Yoshinari Asaoka, Ryosuke Tateishi, Kazuhiko Koike, Hitoshi Arioka, Takuji Okusaka
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 5 Pg. 928-36 (Oct 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24829073 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Drug Combinations
• Indoles
• Oxindoles
• Propionates
• Pyrroles
• S 1 (combination)
• Tegafur
• Oxonic Acid
• orantinib

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Drug Combinations
• Female
• Humans
• Indoles (administration & dosage, adverse effects, pharmacokinetics)
• Liver Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Oxindoles
• Oxonic Acid (administration & dosage, adverse effects, pharmacokinetics)
• Propionates (administration & dosage, adverse effects, pharmacokinetics)
• Pyrroles
• Tegafur (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome