title: Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: results from the expansion cohort of a phase I study.
abstract: BACKGROUND
  Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4 mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).
  
  
  METHODS
  Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4 mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2 weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
  
  
  RESULTS
  Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4 mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ≥20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3 months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept.
  
  
  CONCLUSIONS
  Aflibercept 4 mg/kg plus irinotecan-LV5FU2 every 2 weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.
authors: Medical Oncology Department, Hospital Pitié-Salpêtrière, Paris, France. david.khayat@psl.aphp.fr
authors: David
authors: D
authors: Khayat
authors: Sabine
authors: S
authors: Tejpar
authors: Jean-Philippe
authors: JP
authors: Spano
authors: Chris
authors: C
authors: Verslype
authors: Joël
authors: J
authors: Bloch
authors: Vincent
authors: V
authors: Vandecaveye
authors: Sylvie
authors: S
authors: Assadourian
authors: Karen
authors: K
authors: Soussan-Lazard
authors: Sylvaine
authors: S
authors: Cartot-Coton
authors: Eric
authors: E
authors: Van Cutsem
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D014018:Tissue Distribution
chemical_list: D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000077146:Irinotecan; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin