title: Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study.
abstract: BACKGROUND
  Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases.
  
  
  METHODS
  Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760.
  
  
  RESULTS
  29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6.1, range 1-24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer.
  
  
  CONCLUSIONS
  Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease.
  
  
  BACKGROUND
  Pfizer Global Research and Development.
authors.affiliation: The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.forename: Sophie
authors.initials: S
authors.lastname: Postel-Vinay
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Scott H
authors.initials: SH
authors.lastname: Okuno
authors.forename: Scott M
authors.initials: SM
authors.lastname: Schuetze
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Paccagnella
authors.forename: Gretchen N
authors.initials: GN
authors.lastname: Batzel
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
authors.forename: Francis P
authors.initials: FP
authors.lastname: Worden
authors.forename: Antonio
authors.initials: A
authors.lastname: Gualberto
authors.forename: Michelle
authors.initials: M
authors.lastname: Scurr
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology; D012509:Sarcoma / Q000188:drug therapy*; D012512:Sarcoma, Ewing / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D017526:Receptor, IGF Type 1; C525021:figitumumab