Open AccessPhase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in J apanese patients with solid tumors
Author(s) -
Niwakawa Masashi,
Yamaguchi Raizo,
Onozawa Yusuke,
Yasui Hirofumi,
Taku Keisei,
Naito Tateaki,
Akinaga Shiro,
Boku Narikazu,
Yamamoto Nobuyuki
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12197
Subject(s) - tolerability , medicine , pharmacodynamics , adverse effect , renal cell carcinoma , rash , proteinuria , pharmacokinetics , vascular endothelial growth factor , tyrosine kinase inhibitor , pharmacology , axitinib , oncology , cancer , sunitinib , kidney , vegf receptors
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 J apanese 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 J apanese 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 t 1/2 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 J apanese patients, and was recommended for further clinical trials in the J apanese population. Clinical trial Registration No: Japic CTI ‐090854.