title: Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma.
abstract: OBJECTIVE
  PTK787/ZK 222584 (PTK/ZK; vatalanib), an orally active, multitargeted angiogenesis inhibitor, has shown tolerability and promising activity in early-phase studies, which led to a phase III trial in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4).
  
  
  METHODS
  Patients (N = 1,168) with previously untreated metastatic colorectal cancer were randomly assigned 1:1 to receive FOLFOX4 plus PTK/ZK or placebo (ClinicalTrials.gov identifier: NCT00056459). Stratification factors included WHO performance status (0 v 1 or 2) and serum lactate dehydrogenase (LDH; ≤ v > 1.5× the upper limit of normal). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR).
  
  
  RESULTS
  PFS, OS, and ORR were not statistically improved with PTK/ZK (P > .05). Median PFS by central review was 7.7 months with PTK/ZK versus 7.6 months with placebo (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .118); median OS was 21.4 months with PTK/ZK versus 20.5 months with placebo (HR, 1.08; 95% CI, 0.94 to 1.24; P = .260). In an exploratory post hoc analysis of PFS in patients (n = 158 per arm) with high serum LDH, a potential marker of hypoxia, PFS was longer with PTK/ZK versus placebo (7.7 v 5.8 months, respectively; HR, 0.67; 95% CI, 0.49 to 0.91; P = .009).
  
  
  CONCLUSIONS
  Although the efficacy objectives of this study were not met, a subgroup of patients who may potentially benefit from small-molecule vascular endothelial growth factor receptor inhibitor therapy has been identified and further research is warranted.
authors.affiliation: David Geffen School of Medicine at University of California, Los Angeles, Santa Monica, CA 90404, USA. JRHecht@mednet.ucla.edu
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.forename: Tanja
authors.initials: T
authors.lastname: Trarbach
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.forename: Katherine
authors.initials: K
authors.lastname: Lloyd-Salvant
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.forename: Kelly
authors.initials: K
authors.lastname: Pendergrass
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: Gerold
authors.initials: G
authors.lastname: Meinhardt
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: David
authors.initials: D
authors.lastname: Kerr
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / 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 / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D009944:Organoplatinum Compounds; D010793:Phthalazines; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077150:Oxaliplatin; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil