title: Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials.
abstract: BACKGROUND
  Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases.
  
  
  METHODS
  Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for > or =2 months were categorized as 'non-progressors'. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and C(max) of PTK/ZK on day 1, cycle 1 and clinical outcome.
  
  
  RESULTS
  A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and C(max) was characterized by an E(max) model, suggesting that a change of > or =150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF-A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P=0.027).
  
  
  CONCLUSIONS
  In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.
authors.affiliation: Tumor Biology Center, Freiburg, Germany. drevs@tumorbio.uni-freiburg.de
authors.forename: J
authors.initials: J
authors.lastname: Drevs
authors.forename: U
authors.initials: U
authors.lastname: Zirrgiebel
authors.forename: C I M
authors.initials: CI
authors.lastname: Schmidt-Gersbach
authors.forename: K
authors.initials: K
authors.lastname: Mross
authors.forename: M
authors.initials: M
authors.lastname: Medinger
authors.forename: L
authors.initials: L
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Pinheiro
authors.forename: J
authors.initials: J
authors.lastname: Wood
authors.forename: A L
authors.initials: AL
authors.lastname: Thomas
authors.forename: C
authors.initials: C
authors.lastname: Unger
authors.forename: A
authors.initials: A
authors.lastname: Henry
authors.forename: W P
authors.initials: WP
authors.lastname: Steward
authors.forename: D
authors.initials: D
authors.lastname: Laurent
authors.forename: D
authors.initials: D
authors.lastname: Lebwohl
authors.forename: M
authors.initials: M
authors.lastname: Dugan
authors.forename: D
authors.initials: D
authors.lastname: Marmé
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D015415:Biomarkers; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor