Véronique Diéras1, Hans Wildiers2, Jacek Jassem3, Luc Y Dirix4, Jean-Paul Guastalla5, Petri Bono6, Sara A Hurvitz7, Anthony Gonçalves8, Gilles Romieu9, Steven A Limentani10, Guy Jerusalem11, K C Lakshmaiah12, Henri Roché13, Pedro Sánchez-Rovira14, Tadeusz Pienkowski15, Miguel Ángel Seguí Palmer16, Ai Li17, Yu-Nien Sun18, Cheryl A Pickett19, Dennis J Slamon20. 1. Institut Curie, Paris, France. Electronic address: veronique.dieras@curie.net. 2. University Hospital Leuven, Leuven, Belgium. Electronic address: hans.wildiers@uzleuven.be. 3. Medical University of Gdańsk, Gdańsk, Poland. Electronic address: jjassem@gumed.edu.pl. 4. General Hospital Sint-Augustinus, Antwerp, Belgium. Electronic address: Luc.Dirix@gza.be. 5. Centre Léon Bérard, Lyon, France. Electronic address: GUASTALL@lyon.fnclcc.fr. 6. Helsinki University Central Hospital, Helsinki, Finland. Electronic address: Petri.Bono@hus.fi. 7. UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: SHurvitz@mednet.ucla.edu. 8. Institut Paoli-Calmettes, Marseilles, France. Electronic address: GONCALVESA@marseille.fnclcc.fr. 9. C.R.L.C. Val D'Aurelle, Montpellier, France. Electronic address: gilles@romieu.info. 10. Levine Cancer Institute, Charlotte, NC, USA. Electronic address: Steven.Limentani@carolinashealthcare.org. 11. CHU Sart Tilman, Liege, Belgium. Electronic address: g.jerusalem@chu.ulg.ac.be. 12. Kidwai Memorial Institute of Oncology, Bangalore, India. Electronic address: kcluck@gmail.com. 13. Institut Claudius Régaud, Toulouse, France. Electronic address: Roche.Henri@claudiusregaud.fr. 14. Complejo Hospitalario de Jaén, Jaén, Spain. Electronic address: oncojaen@telefonica.net. 15. European Health Centre Otwock, Warszawa, Poland. Electronic address: tadeusz.pienkowski@gmail.com. 16. Corporació Sanitària Parc Taulí, Sabadell, Spain. Electronic address: MSegui@tauli.cat. 17. Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ail@amgen.com. 18. Amgen Inc., Thousand Oaks, CA, USA. Electronic address: yus@amgen.com. 19. Amgen Inc., Thousand Oaks, CA, USA. Electronic address: cpickett@amgen.com. 20. UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: DSlamon@mednet.ucla.edu.
Abstract
INTRODUCTION: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer. METHODS: Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint. RESULTS: In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively. CONCLUSIONS: There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00511459.
RCT Entities:
INTRODUCTION: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer. METHODS:Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint. RESULTS: In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively. CONCLUSIONS: There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00511459.
Authors: Maren Cam; Manish Charan; Alessandra M Welker; Piyush Dravid; Adam W Studebaker; Jeffrey R Leonard; Christopher R Pierson; Ichiro Nakano; Christine E Beattie; Eugene I Hwang; Madhuri Kambhampati; Javad Nazarian; Jonathan L Finlay; Hakan Cam Journal: Neuro Oncol Date: 2020-03-05 Impact factor: 12.300
Authors: Rajesh Ramanathan; Amy L Olex; Mikhail Dozmorov; Harry D Bear; Leopoldo Jose Fernandez; Kazuaki Takabe Journal: Breast Cancer Res Treat Date: 2017-01-06 Impact factor: 4.872
Authors: Sarah E S Leary; Julie R Park; Joel M Reid; Andrew T Ralya; Sylvain Baruchel; Bing Wu; Timothy P L Roberts; Xiaowei Liu; Charles G Minard; Elizabeth Fox; Brenda Weigel; Susan Blaney Journal: Clin Cancer Res Date: 2017-07-27 Impact factor: 12.531