title: Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors.
abstract: OBJECTIVE
  Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments.
  
  
  METHODS
  Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.
  
  
  RESULTS
  Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (t(max)) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (K(trans) and IAUC(60)) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients.
  
  
  CONCLUSIONS
  Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, the Netherlands. f.eskens@erasmusmc.nl
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Johan L
authors.initials: JL
authors.lastname: Bloem
authors.forename: Olaf
authors.initials: O
authors.lastname: Christensen
authors.forename: Leni
authors.initials: L
authors.lastname: van Doorn
authors.forename: Jan
authors.initials: J
authors.lastname: Ouwerkerk
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: Johan W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Joern
authors.initials: J
authors.lastname: Kraetzschmar
authors.forename: Prabhu
authors.initials: P
authors.lastname: Rajagopalan
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000097:blood; D003287:Contrast Media; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects*; D011724:Pyridazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000097:blood; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D003287:Contrast Media; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533371:telatinib; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3