title: Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study.
abstract: BACKGROUND
  In this randomized phase 2 study, the authors assessed the efficacy and safety of intravenous aflibercept at 2 different doses (2 mg/kg or 4 mg/kg) in patients with recurrent, platinum-resistant ovarian, peritoneal, or fallopian tube cancer who developed disease progression after receiving topotecan and/or pegylated liposomal doxorubicin.
  
  
  METHODS
  Patients were randomized to receive intravenous aflibercept at a dose of either 2 mg/kg or 4 mg/kg every 2 weeks until they developed disease progression or significant toxicity. The primary endpoint was to evaluate Response Evaluation Criteria in Solid Tumor response rates (overall response rate [ORR] = complete responses plus partial responses) and to test the null hypothesis (ORR, >5%). Secondary endpoints included time to tumor progression, safety, progression-free survival/overall survival, drug pharmacokinetics, and immunogenicity. In total, 67 evaluable patients per cohort were planned based on a Simon 2-stage design, and, if those patients responded, then enrollment could extend to 200 patients. Tumor radiographic response was assessed by investigators and by an independent review committee.
  
  
  RESULTS
  After the first 84 evaluable patients, 8 unconfirmed partial responders were noted (ORR, 10%) across both arms; the Independent Data Monitoring Committee recommended continuing blinded accrual. At study completion, 215 evaluable patients were accrued, including 1 responder of 106 patients (0.9%) in the 2-mg/kg cohort and 5 responders of 109 patients (4.6%) in the 4-mg/kg cohort according to the independent review committee. The clinical benefit rate (ORR plus stable disease >6 months) was 12.3% and 11% in the 2-mg/kg and 4-mg/kg cohorts, respectively. Treatment-related grade 3 and 4 adverse events included hypertension (25.5% and 27.5% in the 2-mg/kg and 4-mg/kg cohorts, respectively), proteinuria (9.4% and 7.3%, respectively), and fatigue (5.7% and 3.7%, respectively). The gastrointestinal perforation rate was low (3 patients; 1.4%).
  
  
  CONCLUSIONS
  Aflibercept at a dose of either 2 mg/kg or 4 mg/kg was generally well tolerated but did not meet the primary endpoint for response.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: William P
authors.initials: WP
authors.lastname: Tew
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Josep M
authors.initials: JM
authors.lastname: Del Campo
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.forename: Deolinda
authors.initials: D
authors.lastname: Pereira
authors.forename: Serafina
authors.initials: S
authors.lastname: Mammoliti
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Katia
authors.initials: K
authors.lastname: Tonkin
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Shun
authors.forename: Lars
authors.initials: L
authors.lastname: Sternas
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011788:Quality of Life; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: advanced stage; aflibercept; ovarian cancer; phase 2; platinum resistance