title: Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.
abstract: BACKGROUND
  Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.
  
  
  METHODS
  In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.
  
  
  RESULTS
  Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).
  
  
  CONCLUSIONS
  Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Kliniken Essen Mitte, Essen, Germany. Electronic address: prof.dubois@googlemail.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.affiliation: Department of Gynecologic Oncology and Institute for Cancer Genetics and Informatics, Oslo University Hospital, and Oslo University, Oslo, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kristensen
authors.affiliation: Centre Leon Berard and University of Lyon, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Coordinating Center for Clinical Trials, Marburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Reuss
authors.affiliation: National Cancer Institute of Naples, Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.affiliation: University of Milan Bicocca, Milan, Italy; European Institute of Oncology Milan, Milan, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.affiliation: Health + Life Gesundheitsmanagement GmbH, Vienna, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Denison
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Vall d'Hebron University Hospital Barcelona, Barcelona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Del Campo
authors.affiliation: UMC St Radboud Nijmegen, Nijmegen, Netherlands.
authors.forename: Petronella
authors.initials: P
authors.lastname: Ottevanger
authors.affiliation: West German Tumor Center, Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heubner
authors.affiliation: National Institute of Oncology, Bratislava, Slovakia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Minarik
authors.affiliation: Centre François Baclesse, Comité Uro-Gynécologie, Caen, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sevin
authors.affiliation: Department of Gynecology, University Hospital, Ulm, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: de Gregorio
authors.affiliation: Faculty of Health Science, University of Jan Kochanowski, Kielce, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Bidziński
authors.affiliation: Gynecologic Oncology Center, Kiel, Germany.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Pfisterer
authors.affiliation: University Hospital, Department of Oncology, Lund, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Malander
authors.affiliation: Universitäts-Klinik Schleswig-Holstein (UKSH) Campus Kiel, Department of Gynecology and Obstetrics, Kiel, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Hilpert
authors.affiliation: Rigshospitalet-Copenhagen University Hospital, Department of Oncology, Copenhagen, Denmark.
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.affiliation: Universita Cattolica del Sacro Cuore Policlinico Gemelli, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Evangelisches Krankenhaus, Department of Gynecology and Obstetrics, Duesseldorf, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.affiliation: Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Oncologia MedicaI, Padova, Italy.
authors.forename: Maria O
authors.initials: MO
authors.lastname: Nicoletto
authors.affiliation: Haukeland Universitetssykehus, Bergen, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Bjørge
authors.affiliation: Centre Catherine de Sienne, Nantes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Martin Oliver
authors.initials: MO
authors.lastname: Sailer
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Merger
authors.affiliation: Kliniken Essen Mitte, Essen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Harter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D065426:Cytoreduction Surgical Procedures; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D057194:Intention to Treat Analysis; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D066066:Response Evaluation Criteria in Solid Tumors; D013921:Thrombocytopenia / Q000139:chemically induced; D055815:Young Adult
chemical_list: D007211:Indoles; D016190:Carboplatin; C530716:nintedanib; D017239:Paclitaxel