title: Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent.
  
  
  METHODS
  In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.
  
  
  RESULTS
  Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 microg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t(1/2) of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year.
  
  
  CONCLUSIONS
  Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. teww@mskcc.org
authors.forename: William P
authors.initials: WP
authors.lastname: Tew
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.forename: John
authors.initials: J
authors.lastname: Murren
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.forename: Sandra
authors.initials: S
authors.lastname: Pezzulli
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: David
authors.initials: D
authors.lastname: Mendelson
authors.forename: Lawrence
authors.initials: L
authors.lastname: Schwartz
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.forename: Amanda
authors.initials: A
authors.lastname: Psyrri
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Cedarbaum
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D055103:Hypodermoclysis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor