title: Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion.
  
  
  METHODS
  Patients with documented progressive disease and </=1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m(2)) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H(2) blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF.
  
  
  RESULTS
  Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008).
  
  
  CONCLUSIONS
  SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago Cancer Research Center, Chicago, Illinois, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Susan
authors.initials: S
authors.lastname: Swiger
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Milica
authors.initials: M
authors.lastname: Medved
authors.forename: Greg
authors.initials: G
authors.lastname: Karczmar
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008214:Lymphocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D005947:Glucose