title: A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer.
abstract: BACKGROUND
  This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity.
  
  
  METHODS
  Thirty-five patients received escalating doses of PTK/ZK (range 500-2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage.
  
  
  RESULTS
  Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months.
  
  
  CONCLUSIONS
  The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.
authors.affiliation: Department of Oncology, University of Leicester, Leicester Royal Infirmary, Leicester, UK. at107@le.ac.uk
authors.forename: A L
authors.initials: AL
authors.lastname: Thomas
authors.forename: T
authors.initials: T
authors.lastname: Trarbach
authors.forename: C
authors.initials: C
authors.lastname: Bartel
authors.forename: D
authors.initials: D
authors.lastname: Laurent
authors.forename: A
authors.initials: A
authors.lastname: Henry
authors.forename: M
authors.initials: M
authors.lastname: Poethig
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Masson
authors.forename: W
authors.initials: W
authors.lastname: Steward
authors.forename: U
authors.initials: U
authors.lastname: Vanhoefer
authors.forename: B
authors.initials: B
authors.lastname: Wiedenmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010793:Phthalazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D002955:Leucovorin; D005472:Fluorouracil