title: Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study.
abstract: BACKGROUND
  Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial.
  
  
  METHODS
  In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146.
  
  
  RESULTS
  Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]).
  
  
  CONCLUSIONS
  The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease.
  
  
  BACKGROUND
  Pfizer.
authors.affiliation: University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ioka
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Richard
authors.initials: R
authors.lastname: Létourneau
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Funakoshi
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ohkawa
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Springett
authors.forename: Harpreet S
authors.initials: HS
authors.lastname: Wasan
authors.forename: Peter C
authors.initials: PC
authors.lastname: Trask
authors.forename: Paul
authors.initials: P
authors.lastname: Bycott
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Ricart
authors.forename: Sinil
authors.initials: S
authors.lastname: Kim
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000077784:Axitinib; D003841:Deoxycytidine / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D003841:Deoxycytidine; D000077784:Axitinib; D000093542:Gemcitabine