title: Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma.
abstract: OBJECTIVE
  Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors.
  
  
  METHODS
  Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase ([LDH] ≤ 1.5× the upper limit of normal [ULN] v > 1.5 × ULN). Treatment was given until disease progression or unacceptable toxicity. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK.
  
  
  RESULTS
  No statistically significant differences were seen between the treatment groups for the overall comparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P = .957). Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P = .013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR, 0.63; 95% CI, 0.48 to 0.83; P < .001).
  
  
  CONCLUSIONS
  PTK/ZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTK/ZK was more pronounced in patients with high LDH at baseline.
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Eric.VanCutsem@uz.kuleuven.ac.be
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Emilio
authors.initials: E
authors.lastname: Bajetta
authors.forename: Juan
authors.initials: J
authors.lastname: Valle
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.forename: Malcolm
authors.initials: M
authors.lastname: Moore
authors.forename: Colin
authors.initials: C
authors.lastname: Germond
authors.forename: William
authors.initials: W
authors.lastname: Berg
authors.forename: Bee-Lian
authors.initials: BL
authors.lastname: Chen
authors.forename: Tarja
authors.initials: T
authors.lastname: Jalava
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: Edward
authors.initials: E
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D010793:Phthalazines / Q000008:administration & dosage*; D010919:Placebos; D011725:Pyridines / Q000008:administration & dosage*
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D010793:Phthalazines; D010919:Placebos; D011725:Pyridines; D000077150:Oxaliplatin; C404768:vatalanib; D002955:Leucovorin; D005472:Fluorouracil