title: Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer.
abstract: OBJECTIVE
  Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen.
  
  
  METHODS
  Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS).
  
  
  RESULTS
  In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7-8.6 months] and 2.4 months (95% CI: 1.9-3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6-15.5) and 8.5 months (95% CI: 6.2-10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF.
  
  
  CONCLUSIONS
  Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing.
authors.affiliation: Princess Margaret Phase II Consortium, Toronto, Ontario, Canada.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Tang
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.forename: Georg
authors.initials: G
authors.lastname: Bjarnason
authors.forename: Kiran
authors.initials: K
authors.lastname: Virik
authors.forename: Mary J
authors.initials: MJ
authors.lastname: MacKenzie
authors.forename: Lillian
authors.initials: L
authors.lastname: Lourenco
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor