title: Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial.
abstract: BACKGROUND
  Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival.
  
  
  METHODS
  For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m(2)) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients.
  
  
  RESULTS
  919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]).
  
  
  CONCLUSIONS
  Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Creighton University School of Medicine and University of Arizona Cancer Center at St Joseph's Hospital, Phoenix, AZ, USA. Electronic address: bradley.monk@chw.edu.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.affiliation: Fundacion Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Poveda
authors.affiliation: University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raspagliesi
authors.affiliation: Saitama Medical University International Medical Center, Hidaka-Shi, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Samsung Medical Center, Seoul, South Korea.
authors.forename: Duk-Soo
authors.initials: DS
authors.lastname: Bae
authors.affiliation: Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Oaknin
authors.affiliation: Université Lyon-I, Centre Léon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Provencher
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Gustave Roussy, Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lhommé
authors.affiliation: Cabrini Hospital, Malvern, VIC, Australia.
authors.forename: Gary
authors.initials: G
authors.lastname: Richardson
authors.affiliation: Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: Dolores Gallardo
authors.initials: DG
authors.lastname: Rincón
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Columbia University Medical Center, New York, NY, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.affiliation: Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.affiliation: Riga Eastern Clinical University Hospital, Riga, Latvia.
authors.forename: Arija
authors.initials: A
authors.lastname: Brize
authors.affiliation: Regional Cancer Institute Montpellier, Montpellier, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fabbro
authors.affiliation: University Hospital La Paz, Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Redondo
authors.affiliation: Alexandra Hospital, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Bamias
authors.affiliation: Amgen, Uxbridge, UK.
authors.forename: Marjan
authors.initials: M
authors.lastname: Tassoudji
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Navale
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Warner
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004487:Edema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D028761:Withholding Treatment
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011993:Recombinant Fusion Proteins; D017239:Paclitaxel; C551398:trebananib