title: Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer.
abstract: OBJECTIVE
  PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling.
  
  
  METHODS
  Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response.
  
  
  RESULTS
  At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (K(i)) at day 2 predicted for nonprogression of disease.
  
  
  CONCLUSIONS
  The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK >/= 1,000 mg total daily dose is the biologically active dose.
authors.affiliation: University of Leicester, United Kingdom. AT107@le.ac.uk
authors.forename: Anne L
authors.initials: AL
authors.lastname: Thomas
authors.forename: Bruno
authors.initials: B
authors.lastname: Morgan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Horsfield
authors.forename: Anthony
authors.initials: A
authors.lastname: Higginson
authors.forename: Andrea
authors.initials: A
authors.lastname: Kay
authors.forename: Lucy
authors.initials: L
authors.lastname: Lee
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.forename: Marie
authors.initials: M
authors.lastname: Puccio-Pick
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D016009:Chi-Square Distribution; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010793:Phthalazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib