Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors.

Abstract

Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase I study was designed to determine the recommended phase II dose of tivozanib for Japanese patients; secondary objectives included pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3-weeks-on/1-week-off cycle was examined in nine Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 mg; Level 2, 1.5 mg). No dose-limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug-related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade ≥3, hand-foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well-manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of plasma VEGF and decrease of plasma VEGFR-1 and VEGFR-2 were observed 1-3 weeks after tivozanib treatment. Although no complete or partial response was observed, long-term stable disease continuing more than 170 days was observed in three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In conclusion, 1.5 mg/day of tivozanib in a 3-weeks-on/1-week-off setting was tolerable in Japanese patients, and was recommended for further clinical trials in the Japanese population. Clinical trial Registration No: JapicCTI-090854.

• Authors: Masashi Niwakawa, Raizo Yamaguchi, Yusuke Onozawa, Hirofumi Yasui, Keisei Taku, Tateaki Naito, Shiro Akinaga, Narikazu Boku, Nobuyuki Yamamoto
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 8 Pg. 1039-44 (Aug 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23679664 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinolines
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• tivozanib
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Antineoplastic Agents (adverse effects, therapeutic use)
• Asian People
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (blood, drug therapy, enzymology)
• Phenylurea Compounds (adverse effects, therapeutic use)
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Quinolines (adverse effects, therapeutic use)
• Treatment Outcome
• Vascular Endothelial Growth Factor A (blood)
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, blood)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, blood)