Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: Results of a randomized, double-blind, phase 2, parallel-arm study

Authors


  • We thank the patients who participated in the study. We also thank the principal investigators and their teams: Australia: Paul Mainwaring (Mater Adult Hospital Brisbane Division of Cancer Services, South Brisbane, Queensland), Philip Clingan (Southern Medical Day Care, Wollongong, New South Wales), Michael Friedlander (Department of Medical Oncology, Randwick, New South Wales), and Danny Rischin (Mercy Hospital for Women, Heidelberg, Victoria); Canada: Amit Oza (Princess Margaret Hospital, Toronto, Ontario), Katia Tonkin (Cross Cancer Institute, Edmonton, Alberta), Michel Roy (CHUQ-Hotel-Dieu de Quebec, Quebec), Suzie Lau (McGill University, Montreal, Quebec), and Praful Ghatage (Tom Baker Cancer Center, Calgary, Alberta); France: Isabelle Ray-Coquard (Oncologie Medicale Centre Leon Berard, Lyon) and Eric Pujade-Lauraine (Hopital Hotel Dieu, Paris); Germany: Andreas Schneeweiss (Universitats-Frauenklinik, Heidelberg), Michael Clemens (Krankenhausanstalten Mutterhaus de Borromaerinnen, Trier), and Pauline Wimberger (Universitats-Frauenklinik Essen AoR, Essen); Italy: Nicoletta Colombo (Istituto Europeo di Oncologia, Milan), Andrea Lissoni (Ospedale S. Gerado, Monza), Pierluigi Panici (Policlinico Umberto I Dipartimento di Scienze Ginecologiche, Perinatologia e Puericultura, Rome), Lucio Crino (Ospedale Silvestrini, Perugia), Dionyssios Katsaros (Universita di Torino, Torino), Giovanni Scambia (Universita Cattolica de Sacro Cuore, Campobasso), Alberto Sobrero (Ospedale San Martino, Genova), and Pierfranco Conte (Policlinico di Modena, Modena); the Netherlands: Klaas Hoekman (VU Medisch Centrum de Boelelaan, Amsterdam); Portugal: Deolinda Pereira (Instituto Portugues de Oncologia de Porto Francisco Gentil, Porto) and Fatima Vaz (Instituto Portugues de Oncologia de Lisboa Francisco Gentil, Lisbon); Spain: Ana Oaknin (Institut Catala d'Oncologia, Barcelona), Jose Del Campo (Hospital Vall d'Hebron, Barcelona), Isabel Bover (Hospital Son Llatzer, Palma de Mallorca), and Antonio Gonzalez-Martin (Hospital Ramon y Cajal, Madrid); Sweden: Bengt Tholander (Karolinska Universitetssjukhuset Solna, Stockholm); Switzerland: Cristina Sessa (Istituto Oncologico della Svizzera Italiana, Bellinzona), Edward Wight (Leitender Arzt-Gynakologie Klinik, Basel), Roger Von Moos (Raterisches Kantons und Regionalspital, Loestrasse), and Astrid Schoenenberger (Leitende Aertzin Onkologie, Tellstrasse); United States: Sharad Ghamande (Medical College of Georgia, Augusta, Ga), Ellen Smith (Southwest Regional Cancer Center, Austin, Tex), Michael Gold (University of Oklahoma College of Medicine, Oklahoma City, Okla), Daniela Matei (Indiana University Cancer Center, Indianapolis, Ind), Howard Homesley (Brody School of Medicine at East Carolina University, Greenville, NC), Stephen Andrews (University of Toledo, Toledo, Ohio), Henry Sprance (Jersey Shore University Medical Center, Neptune, NJ), William McGuire (Harry and Jeanette Weinberg Cancer Institute at Franklin Square, Baltimore, Md), Ralph Boccia (Center for Cancer and Blood Disorders, Bethesda, Md), Robert Edwards (Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, Pa), Benjamin Greer (University of Washington Medical Center, Seattle, Wash), Dennis Scribner (Carilion GYN Oncology Associates, Roanoke, Va), Nashat Gabrail (Gabrail Cancer Center, Canton, Ohio), and William Tew (Memorial Sloan-Kettering Cancer Center, New York, NY).

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. Cancer 2014;120:335–343. © 2013 American Cancer Society.

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