title: Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas.
abstract: OBJECTIVE
  SU5416 (semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor-2 and KIT receptor tyrosine kinases. This Phase II study was conducted to investigate the safety and efficacy of SU5416 for patients with soft tissue sarcomas.
  
  
  METHODS
  Thirteen patients with locally advanced or metastatic soft tissue sarcomas were treated with SU5416 via intravenous infusion at a dose of 145 mg/m(2) twice weekly. In selected cases tumor biopsies were taken before and after 2 months of treatment.
  
  
  RESULTS
  The median progression-free survival was 1.8 months. Median overall survival was 22.8 months. No objective tumor responses were observed. There was evidence of shorter survival among patients with high baseline urine VEGF levels (P = 0.04). No grade 4 toxicities were observed. The most common grade 3 toxicities were headache and thrombosis. Other less serious toxicities included fatigue, nausea, and abdominal pain. The median systolic blood pressure increased from 118 mmHg at baseline to 133 after 1 month of treatment (P = 0.01). Post-treatment tumor biopsies showed no significant decreases in VEGF receptor phosphorylation compared with baseline in 3 evaluable patients. One patient with gastrointestinal stromal tumor who had rapid progression during SU5416 treatment was subsequently treated with another KIT inhibitor, imatinib mesylate, and had a partial response lasting >36 months.
  
  
  CONCLUSIONS
  SU5416 was relatively well tolerated but did not demonstrate significant antitumor activity against advanced soft tissue sarcoma. Correlative studies suggest that VEGF receptor or KIT inhibition was incomplete in at least some cases, providing a possible explanation for the observed lack of activity.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
authors.forename: Judith
authors.initials: J
authors.lastname: Manola
authors.forename: Darren W
authors.initials: DW
authors.lastname: Davis
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: David
authors.initials: D
authors.lastname: Harmon
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Geraldine
authors.initials: G
authors.lastname: Goss
authors.forename: Travis
authors.initials: T
authors.lastname: Quigley
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Silverman
authors.forename: Susan
authors.initials: S
authors.lastname: Connors
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012449:Safety; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000652:urine
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; D019009:Proto-Oncogene Proteins c-kit; D040262:Receptors, Vascular Endothelial Growth Factor