title: A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer.
abstract: OBJECTIVE
  To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline).
  
  
  RESULTS
  Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels.
  
  
  CONCLUSIONS
  The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.
authors.affiliation: British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada.
authors.forename: Arun A
authors.initials: AA
authors.lastname: Azad
authors.forename: Emma K
authors.initials: EK
authors.lastname: Beardsley
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ellard
authors.forename: Lawrence
authors.initials: L
authors.lastname: Klotz
authors.forename: Joseph
authors.initials: J
authors.lastname: Chin
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.forename: Som D
authors.initials: SD
authors.lastname: Mukherjee
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
mesh_terms: D000368:Aged; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D010880:Piperidines / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014105:Tosyl Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C053541:bicalutamide; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D017430:Prostate-Specific Antigen; C452423:vandetanib