1. 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
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Ignace Vergote, Giovanni Scambia, David M O'Malley, Ben Van Calster, Sang-Yoon Park, Josep M del Campo, Werner Meier, Aristotelis Bamias, Nicoletta Colombo, Robert M Wenham, Al Covens, Christian Marth, Mansoor Raza Mirza, Judith R Kroep, Haijun Ma, Cheryl A Pickett, Bradley J Monk, Sang Yoon Park, Yong Sang Song, Yulia Makarova, Joshua Trinidad, Hextan Yuen Sheung Ngan, Gerasimos Aravantinos, Joo-Hyun Nam, Vera Gorbunova, Ludmila Krikunova, Duk-Soo Bae, Jose Angel Arranz Arija, Claudio Zamagni, Christos Papandreou, Francesco Raspagliesi, Alla Lisyanskaya, Ana Oaknin Benzaquen, Germana Tognon, Eugenia Ortega, Antonio Casado Herraez, Joseph Buscema, Andrew Green, Robert Burger, Dina Sakaeva, Andres Redondo Sanchez, Sharad Ghamande, Laurel King, Edgar Petru, Ulla Peen, Satoshi Takeuchi, Kimio Ushijima, Antonio Gonzalez Martin, Scott Kamelle, Michael Carney, Frédéric Forget, James Bentley, Jalid Sehouli, Paolo Zola, Hidenori Kato, Natalya Fadeeva, Evgeny Gotovkin, Vladimir Vladimirov, Margarita Romeo Marin, Eva Guerra Alia, Mark Shahin, Snehalkumar Bhoola, Krishnansu Tewari, Daniel Anderson, Brigitte Honhon, Joseph (Gino) Pelgrims, Amit Oza, Jesus Garcia-Donas Jimenez, Vincent Hansen, David O'Malley, Ivor Benjamin, Vincent Renard, Heidi Van den Bulck, Claudia Haenle, Georgios Koumakis, Harushige Yokota, Vadim Popov, William Bradley, Robert Wenham, Robert Reid, Donna McNamara, Richard Friedman, Joyce Barlin, Nicola Spirtos, Julia Chapman, Paul Sevelda, Manon Huizing, Caroline Lamot, Frédéric Goffin, Lionel D Hondt, Allan Covens, Silvana Spadafora, Beate Rautenberg, Toralf Reimer, Volker Möbus, Felix Hilpert, Martina Gropp-Meier, Antonella Savarese, Sandro Pignata, Francesco Verderame, Mika Mizuno, Hirokuni Takano, Petronella Ottevanger, Andres Poveda Velasco, Isabel Palacio-Vazquez, Amy Law, Kristi McIntyre, Michael Teneriello, Abbie Fields, Samuel Lentz, Daron Street, Benjamin Schwartz, Robert Mannel, Peter Lim, Heather Pulaski, Wolfgang Janni, Andreas Zorr, Ulrich Karck, Ashley Chi Kin Cheng, Roberto Sorio, Cesare Gridelli, Daisuke Aoki, Tetsuro Oishi, Yasuyuki Hirashima, Ingrid Boere, Esther Falco Ferrer, Patricia Braly, Sharon Wilks, Christine Lee, Jeanne Schilder, Dan Veljovich, Angeles Secord, Kevin Davis, Luis Rojas-Espaillat, Shashikant Lele, Stephen DePasquale, Robert Squatrito, Christian Schauer, Luc Dirix, Peter Vuylsteke, Eric Joosens, Diane Provencher, Hans-Joachim Lueck, Alexander Hein, Alexander Burges, Ulrich Canzler, Tjoung-Won Park-Simon, Frank Griesinger, Angiolo Gadducci, Oscar Alabiso, Aikou Okamoto, Takashi Sawasaki, Toshiaki Saito, Ana Herrero Ibañez, Coralia Calomeni, Monique Spillman, Janak Choksi, Nicholas Taylor, Carolyn Muller, David Moore, Paul DiSilvestro, Mary Cunningham, Peter Rose, Peter Oppelt, Didier Verhoeven, Marie-Pascale Graas, Prafull Ghatage, Katia Tonkin, Christian Kurzeder, Benjamin Schnappauf, Volkmar Müller, Hannah Schmalzrie, Haralambos Kalofonos, Milena Bruzzone, Judith Kroep, Cristina Caballero Diaz, Jeronimo Martinez Garcia, Susana Hernando Polo, Mitchell Garrison, Rodney Rocconi, Stephen Andrews, Robert Bristow, Michael McHale, Jack Basil, William Houck III, Maria Bell, Jonathan Cosin, Susan Modesitt, James Kendrick, James Wade III, Cheung Wong, Anthony Evans, Thomas Buekers, Timothy Vanderkwaak, James Ferriss, Christopher Darus, Stacy DAndre, Robert Higgins, Bradley Monk, Jamie Bakkum-Gamez, Leslie DeMars, Linda Van Le, Larry Puls, Shruti Trehan, James LaPolla, Elizabeth Dickson Michelson, Joseph Merchant, Christopher Peterson, Gary Reid, Donald Seago, Susan Zweizig, Walter Gajewski, Amit Panwalkar, Rudolf Leikermoser, Gerhard Bogner, Philip Debruyne, Randal D'hondt, Patrick Berteloot, Joseph Kerger, James Biagi, Vincent Castonguay, Stephen Welch, Aida Muhic, Martin Heubner, Eva-Maria Grischke, Brigitte Rack, Markus Fleisch, Florian Lordick, Dimitrios Pectasides, Wing Ming Ho, Luigi Selvaggi, Flavia Morales Vasquez, William Orlando Brito Villanueva, Alejandro Molina Alavez, Lonneke Kessels, Ana Santaballa Bertran, Cesar Mendiola Fernandez, Miguel Beltran Fabregat, Salvatore Del Prete, John Elkas, Gary Cecchi, Pallavi Kumar, Warner Huh, Mark Messing, Misagh Karimi, Ann Kelley, Babak Edraki, David Mutch, Gary Leiserowitz, Jeanne Anderson, Scott Lentz, Setsuko Chambers, Robert Morris, Steven Waggoner, Alan Gordon, Michael Method, Peter Johnson, Raymond Lord, Janet Drake, Kulumani Sivarajan, Madhu Midathada, Kristen Rice, Troy Wadsworth, James Pavelka, Robert Edwards, David Scott Miller, Patricia Locantore Ford, Jean Hurteau, David Bender, Veronica Schimp, William Creasman, Rachel Lerner, Donald Chamberlain, Angela Kueck, John McDonald, Salman Malad, Bernice Robinson-Bennett, Susan Davidson, Thomas Krivak, Timothy Lestingi, Hector Arango, Paul Berard, Karen Finkelstein, Rakesh Gaur, Carolyn Krasner, Frederick Ueland, Lance Talmage, Seiko Yamada, Gregory Sutton, Ronald Potkul, Monica Prasad-Hayes, Janet Osborne, Paul Celano, James Thigpen, Sudarshan Sharma, Russell Schilder, Jonathan Tammela, Mary Kemeny, Amy Brown, Eric Eisenhauer, James Williams, Kendrith Rowland, Kenneth Nahum, James Burke, Zahid Dar, Nicole Fleming, Randall Gibb, Alfred Guirguis, Thomas Herzog, Veena John, Santhosh Kumar, Aparna Kamat, Mohamad Kassar, Mario Leitao, Lyuba Levine, Luis Mendez, Dhimant Patel, Emily Berry, David Warshal, Judith Wolf, Corrine Zarwan, Yvonne Collins, Gary Spitzer, Brigitte Miller, Mark Einstein, Medical Oncology, Molecular Genetics, Vergote, I, Scambia, G, O'Malley, D, Van Calster, B, Park, S, Del Campo, J, Meier, W, Bamias, A, Colombo, N, Wenham, R, Covens, A, Marth, C, Raza Mirza, M, Kroep, J, Ma, H, Pickett, C, and Monk, B
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0301 basic medicine ,medicine.medical_specialty ,Paclitaxel ,Recombinant Fusion Proteins ,Population ,Phases of clinical research ,Carcinoma, Ovarian Epithelial ,Placebo ,Gastroenterology ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Maintenance therapy ,SDG 3 - Good Health and Well-being ,TRINOVA-3/ENGOT-ov2/GOG-3001 investigators ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Fallopian Tube Neoplasms ,Humans ,Progression-free survival ,education ,Survival rate ,Peritoneal Neoplasms ,Aged ,Ovarian Neoplasms ,Salvage Therapy ,education.field_of_study ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Survival Rate ,ovarian cancer ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Female ,business ,Febrile neutropenia ,Follow-Up Studies - 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. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published
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- 2019