title: A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors.
abstract: OBJECTIVE
  Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis.
  
  
  METHODS
  Patients with refractory solid tumors, Karnofsky performance status ≥70%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment.
  
  
  RESULTS
  Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted.
  
  
  CONCLUSIONS
  Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Box 3052, Durham, NC, USA.
authors.forename: Hope E
authors.initials: HE
authors.lastname: Uronis
authors.forename: Jingquan
authors.initials: J
authors.lastname: Jia
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Leigh
authors.initials: L
authors.lastname: Howard
authors.forename: Neal A
authors.initials: NA
authors.lastname: Ready
authors.forename: Paula H
authors.initials: PH
authors.lastname: Lee
authors.forename: Mark D
authors.initials: MD
authors.lastname: Starr
authors.forename: Andrew
authors.initials: A
authors.lastname: Dellinger
authors.forename: Herbert
authors.initials: H
authors.lastname: Pang
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D051419:Paxillin / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D051419:Paxillin; D000068258:Bevacizumab; C486839:intetumumab