title: Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.
abstract: OBJECTIVE
  To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor.
  
  
  METHODS
  Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors.
  
  
  RESULTS
  Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors.
  
  
  CONCLUSIONS
  Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.
authors: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. f.eskens@erasmusmc.nl
authors: Ferry A L M
authors: FA
authors: Eskens
authors: Maja J A
authors: MJ
authors: de Jonge
authors: Pankaj
authors: P
authors: Bhargava
authors: Toshiyuki
authors: T
authors: Isoe
authors: Monette M
authors: MM
authors: Cotreau
authors: Brooke
authors: B
authors: Esteves
authors: Kunihiko
authors: K
authors: Hayashi
authors: Herman
authors: H
authors: Burger
authors: Maarten
authors: M
authors: Thomeer
authors: Leni
authors: L
authors: van Doorn
authors: Jaap
authors: J
authors: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3