title: Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2.
abstract: OBJECTIVE
  To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer.
  
  
  METHODS
  A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples.
  
  
  RESULTS
  Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed.
  
  
  CONCLUSIONS
  Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1906, USA. annunzic@mail.nih.gov
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walker
authors.forename: Lori
authors.initials: L
authors.lastname: Minasian
authors.forename: Minshu
authors.initials: M
authors.lastname: Yu
authors.forename: Herbert
authors.initials: H
authors.lastname: Kotz
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
authors.forename: Katherine
authors.initials: K
authors.lastname: Calvo
authors.forename: Peter
authors.initials: P
authors.lastname: Choyke
authors.forename: Daniel
authors.initials: D
authors.lastname: Kimm
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D017211:Treatment Failure; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib