title: S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors.
abstract: CONCLUSIONS
  Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study.
  
  
  BACKGROUND
  Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis.
  
  
  METHODS
  Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST.
  
  
  RESULTS
  S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia.
  
  
  CONCLUSIONS
  No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.
authors.affiliation: SWOG Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA blankec@ohsu.edu.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: SWOG Statistical Center, Seattle, Washington, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Rankin
authors.affiliation: Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Corless
authors.affiliation: University of Washington, Seattle, Washington, USA.
authors.forename: Janet F
authors.initials: JF
authors.lastname: Eary
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Mulder
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Okuno
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.affiliation: Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Heinrich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D000068258:Bevacizumab; D000068877:Imatinib Mesylate