title: Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial.
abstract: OBJECTIVE
  We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity.
  
  
  METHODS
  Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B).
  
  
  RESULTS
  Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P<0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell-derived factor-1 was associated with PFS6 success (P=0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P=0.022). Imaging analysis showed a trend associating ADC-L with poor outcome.
  
  
  CONCLUSIONS
  The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA. galanis.evanthia@ayo.edu
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: S Keith
authors.initials: SK
authors.lastname: Anderson
authors.forename: Jackie M
authors.initials: JM
authors.lastname: Lafky
authors.forename: Joon H
authors.initials: JH
authors.lastname: Uhm
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Kimlinger
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Flynn
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kaufmann
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009360:Neoplastic Cells, Circulating; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2