@article{3105962,
    title = "Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial",
    author = "Vergote, I. and Scambia, G. and O'Malley, D.M. and Van Calster, B. and Park, S.-Y. and del Campo, J.M. and Meier, W. and Bamias, A. and Colombo, N. and Wenham, R.M. and Covens, A. and Marth, C. and Raza Mirza, M. and Kroep, J.R. and Ma, H. and Pickett, C.A. and Monk, B.J. and Park, S.Y. and Song, Y.S. and Makarova, Y. and Trinidad, J. and Ngan, H.Y.S. and Aravantinos, G. and Nam, J.-H. and Gorbunova, V. and Krikunova, L. and Bae, D.-S. and Arija, J.A.A. and Mirza, M.R. and Zamagni, C. and Papandreou, C. and Raspagliesi, F. and Lisyanskaya, A. and Benzaquen, A.O. and Tognon, G. and Ortega, E. and Herraez, A.C. and Buscema, J. and Green, A. and Burger, R. and Sakaeva, D. and Sanchez, A.R. and Ghamande, S. and King, L. and Petru, E. and Peen, U. and Takeuchi, S. and Ushijima, K. and Martin, A.G. and Kamelle, S. and Carney, M. and Forget, F. and Bentley, J. and Sehouli, J. and Zola, P. and Kato, H. and Fadeeva, N. and Gotovkin, E. and Vladimirov, V. and Marin, M.R. and Alia, E.G. and Shahin, M. and Bhoola, S. and Tewari, K. and Anderson, D. and Honhon, B. and Pelgrims, J.G. and Oza, A. and Jimenez, J.G.-D. and Hansen, V. and Benjamin, I. and Renard, V. and Van den Bulck, H. and Haenle, C. and Koumakis, G. and Yokota, H. and Popov, V. and Bradley, W. and Wenham, R. and Reid, R. and McNamara, D. and Friedman, R. and Barlin, J. and Spirtos, N. and Chapman, J. and Sevelda, P. and Huizing, M. and Lamot, C. and Goffin, F. and Hondt, L.D. and Covens, A. and Spadafora, S. and Rautenberg, B. and Reimer, T. and Möbus, V. and Hilpert, F. and Gropp-Meier, M. and Savarese, A. and Pignata, S. and Verderame, F. and Mizuno, M. and Takano, H. and Ottevanger, P. and Velasco, A.P. and Palacio-Vazquez, I. and Law, A. and McIntyre, K. and Teneriello, M. and Fields, A. and Lentz, S. and Street, D. and Schwartz, B. and Mannel, R. and Lim, P. and Pulaski, H. and Janni, W. and Zorr, A. and Karck, U. and Cheng, A.C.K. and Sorio, R. and Gridelli, C. and Aoki, D. and Oishi, T. and Hirashima, Y. and Boere, I. and Ferrer, E.F. and Braly, P. and Wilks, S. and Lee, C. and Schilder, J. and Veljovich, D. and Secord, A. and Davis, K. and Rojas-Espaillat, L. and Lele, S. and DePasquale, S. and Squatrito, R. and Schauer, C. and Dirix, L. and Vuylsteke, P. and Joosens, E. and Provencher, D. and Lueck, H.-J. and Hein, A. and Burges, A. and Canzler, U. and Park-Simon, T.-W. and Griesinger, F. and Gadducci, A. and Alabiso, O. and Okamoto, A. and Sawasaki, T. and Saito, T. and Ibañez, A.H. and Calomeni, C. and Spillman, M. and Choksi, J. and Taylor, N. and Muller, C. and Moore, D. and DiSilvestro, P. and Cunningham, M. and Rose, P. and Oppelt, P. and Verhoeven, D. and Graas, M.-P. and Ghatage, P. and Tonkin, K. and Kurzeder, C. and Schnappauf, B. and Müller, V. and Schmalzrie, H. and Kalofonos, H. and Bruzzone, M. and Kroep, J. and Diaz, C.C. and Garcia, J.M. and Polo, S.H. and Garrison, M. and Rocconi, R. and Andrews, S. and Bristow, R. and McHale, M. and Basil, J. and Houck III, W. and Bell, M. and Cosin, J. and Modesitt, S. and Kendrick, J. and Wade III, J. and Wong, C. and Evans, A. and Buekers, T. and Vanderkwaak, T. and Ferriss, J. and Darus, C. and DAndre, S. and Higgins, R. and Monk, B. and Bakkum-Gamez, J. and DeMars, L. and Van Le, L. and Puls, L. and Trehan, S. and LaPolla, J. and Michelson, E.D. and Merchant, J. and Peterson, C. and Reid, G. and Seago, D. and Zweizig, S. and Gajewski, W. and Panwalkar, A. and Leikermoser, R. and Bogner, G. and Debruyne, P. and D'hondt, R. and Berteloot, P. and Kerger, J. and Biagi, J. and Castonguay, V. and Welch, S. and Muhic, A. and Heubner, M. and Grischke, E.-M. and Rack, B. and Fleisch, M. and Lordick, F. and Pectasides, D. and Ho, W.M. and Selvaggi, L. and Vasquez, F.M. and Villanueva, W.O.B. and Alavez, A.M. and Kessels, L. and Bertran, A.S. and Fernandez, C.M. and Fabregat, M.B. and Del Prete, S. and Elkas, J. and Cecchi, G. and Kumar, P. and Huh, W. and Messing, M. and Karimi, M. and Kelley, A. and Edraki, B. and Mutch, D. and Leiserowitz, G. and Anderson, J. and Lentz, S. and Chambers, S. and Morris, R. and Waggoner, S. and Gordon, A. and Method, M. and Johnson, P. and Lord, R. and Drake, J. and Sivarajan, K. and Midathada, M. and Rice, K. and Wadsworth, T. and Pavelka, J. and Edwards, R. and Miller, D.S. and Ford, P.L. and Hurteau, J. and Bender, D. and Schimp, V. and Creasman, W. and Lerner, R. and Chamberlain, D. and Kueck, A. and McDonald, J. and Malad, S. and Robinson-Bennett, B. and Davidson, S. and Krivak, T. and Lestingi, T. and Arango, H. and Berard, P. and Finkelstein, K. and Gaur, R. and Krasner, C. and Ueland, F. and Talmage, L. and Yamada, S. and Sutton, G. and Potkul, R. and Prasad-Hayes, M. and Osborne, J. and Celano, P. and Thigpen, J. and Sharma, S. and Schilder, R. and Tammela, J. and Kemeny, M. and Brown, A. and Eisenhauer, E. and Williams, J. and Rowland, K. and Nahum, K. and Burke, J. and Dar, Z. and Fleming, N. and Gibb, R. and Guirguis, A. and Herzog, T. and John, V. and Kumar, S. and Kamat, A. and Kassar, M. and Leitao, M. and Levine, L. and Mendez, L. and Patel, D. and Berry, E. and Warshal, D. and Wolf, J. and Zarwan, C. and Collins, Y. and Spitzer, G. and Miller, B. and Einstein, M. and TRINOVA-3/ENGOT-ov2/GOG-3001 investigators",
    journal = "The lancet oncology",
    year = "2019",
    volume = "20",
    number = "6",
    pages = "862-876",
    publisher = "Elsevier Ireland Ltd",
    doi = "10.1016/S1470-2045(19)30178-0",
    keywords = "carboplatin;  paclitaxel;  placebo;  trebananib;  antineoplastic agent;  carboplatin;  fusion protein;  paclitaxel;  trebananib, abdominal distension;  abdominal pain;  adult;  advanced cancer;  aged;  alopecia;  anemia;  area under the curve;  arthralgia;  Article;  ascites;  asthenia;  backache;  blurred vision;  cancer center;  cancer combination chemotherapy;  cancer staging;  cancer survival;  colitis;  constipation;  controlled study;  coughing;  decreased appetite;  diarrhea;  disease severity;  dizziness;  double blind procedure;  drug dose reduction;  drug efficacy;  drug safety;  drug withdrawal;  dysgeusia;  dyspepsia;  dyspnea;  edema;  fatigue;  febrile neutropenia;  female;  fever;  follow up;  functional status;  generalized edema;  headache;  health;  human;  human cell;  human tissue;  hypokalemia;  hypomagnesemia;  insomnia;  leukocyte count;  leukopenia;  limb pain;  lung infection;  lymphedema;  maintenance therapy;  major clinical study;  multiple cycle treatment;  musculoskeletal pain;  myalgia;  nausea;  neutropenia;  neutrophil count;  ovary cancer;  ovary carcinoma;  pain;  paresthesia;  peripheral neuropathy;  peritoneum cancer;  phase 3 clinical trial;  plasma concentration-time curve;  platelet count;  pleura effusion;  primary tumor;  priority journal;  progression free survival;  pruritus;  randomized controlled trial;  rash;  sensory neuropathy;  side effect;  survival rate;  survival time;  thrombocytopenia;  tumor biopsy;  upper abdominal pain;  urinary tract infection;  uterine tube tumor;  vomiting;  clinical trial;  middle aged;  multicenter study;  ovary tumor;  pathology;  peritoneum tumor;  prognosis;  salvage therapy;  uterine tube tumor, Aged;  Antineoplastic Combined Chemotherapy Protocols;  Carboplatin;  Carcinoma, Ovarian Epithelial;  Double-Blind Method;  Fallopian Tube Neoplasms;  Female;  Follow-Up Studies;  Humans;  Middle Aged;  Ovarian Neoplasms;  Paclitaxel;  Peritoneal Neoplasms;  Prognosis;  Recombinant Fusion Proteins;  Salvage Therapy;  Survival Rate",
    abstract = "Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen. © 2019 Elsevier Ltd"
}