PMID- 25163906 OWN - NLM STAT- MEDLINE DCOM- 20150114 LR - 20230202 IS - 1474-5488 (Electronic) IS - 1470-2045 (Linking) VI - 15 IP - 10 DP - 2014 Sep TI - Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. PG - 1100-8 LID - S1470-2045(14)70379-1 [pii] LID - 10.1016/S1470-2045(14)70379-1 [doi] AB - BACKGROUND: Cilengitide is a selective alphavbeta3 and alphavbeta5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age >/=18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26.3 months (95% CI 23.8-28.8) in the cilengitide group and 26.3 months (23.9-34.7) in the control group (hazard ratio 1.02, 95% CI 0.81-1.29, p=0.86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Stupp, Roger AU - Stupp R AD - UniversitatsSpital Zurich, Zurich, Switzerland; Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Electronic address: roger.stupp@usz.ch. FAU - Hegi, Monika E AU - Hegi ME AD - Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. FAU - Gorlia, Thierry AU - Gorlia T AD - EORTC Headquarters, Brussels, Belgium. FAU - Erridge, Sara C AU - Erridge SC AD - Edinburgh Cancer Centre, University of Edinburgh, Edinburgh, UK. FAU - Perry, James AU - Perry J AD - Sunnybrook Health Sciences Centre, Toronto, ON, Canada. FAU - Hong, Yong-Kil AU - Hong YK AD - The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea. FAU - Aldape, Kenneth D AU - Aldape KD AD - The University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Lhermitte, Benoit AU - Lhermitte B AD - Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. FAU - Pietsch, Torsten AU - Pietsch T AD - Department of Neuropathology, Universitat Bonn, Bonn, Germany. FAU - Grujicic, Danica AU - Grujicic D AD - Clinic for Neurosurgery, Clinical Center Serbia and Medical Faculty University of Belgrade, Belgrade, Serbia. FAU - Steinbach, Joachim Peter AU - Steinbach JP AD - Klinikum der J W Goethe Universitat Frankfurt, Frankfurt, Germany. FAU - Wick, Wolfgang AU - Wick W AD - Heidelberg University Medical Center & German Cancer Research Center, Heidelberg, Germany. FAU - Tarnawski, Rafal AU - Tarnawski R AD - Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, Gliwice, Poland. FAU - Nam, Do-Hyun AU - Nam DH AD - Samsung Medical Center, Sungkyunkwan Univ School of Medicine, Seoul, South Korea. FAU - Hau, Peter AU - Hau P AD - Universitatsklinikum Regensburg, Regensburg, Germany. FAU - Weyerbrock, Astrid AU - Weyerbrock A AD - Universitatsklinikum Freiburg, Freiburg, Germany. FAU - Taphoorn, Martin J B AU - Taphoorn MJ AD - Medical Center Haaglanden, The Hague, Netherlands. FAU - Shen, Chiung-Chyi AU - Shen CC AD - Taichung Veterans General Hospital, Taichung, Taiwan. FAU - Rao, Nalini AU - Rao N AD - Bangalore Institute of Oncology, Bangalore, India. FAU - Thurzo, Laszlo AU - Thurzo L AD - Szegedi Tudomanyegyetem, Szeged, Hungary. FAU - Herrlinger, Ulrich AU - Herrlinger U AD - Department of Neuropathology, Universitat Bonn, Bonn, Germany. FAU - Gupta, Tejpal AU - Gupta T AD - Tata Memorial Centre, Navi Mumbai, India. FAU - Kortmann, Rolf-Dieter AU - Kortmann RD AD - Universitatsklinikum Leipzig, Leipzig, Germany. FAU - Adamska, Krystyna AU - Adamska K AD - Greater Poland Cancer Centre, Poznan, Poland. FAU - McBain, Catherine AU - McBain C AD - The Christie NHS FT, Manchester, UK. FAU - Brandes, Alba A AU - Brandes AA AD - Bellaria-Maggiore Hospital, AUSL-IRCCS Institute of Neurological Sciences-Bologna, Italy. FAU - Tonn, Joerg Christian AU - Tonn JC AD - Klinikum der Universitat Munchen, Munchen, Germany. FAU - Schnell, Oliver AU - Schnell O AD - Klinikum der Universitat Munchen, Munchen, Germany. FAU - Wiegel, Thomas AU - Wiegel T AD - University Hospital Ulm, Ulm, Germany. FAU - Kim, Chae-Yong AU - Kim CY AD - Seoul National University Bundang Hospital, SNU College of Medicine, Seoul, South Korea. FAU - Nabors, Louis Burt AU - Nabors LB AD - University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Reardon, David A AU - Reardon DA AD - Dana-Farber Cancer Institute, Boston, MA, USA. FAU - van den Bent, Martin J AU - van den Bent MJ AD - Erasmus MC-Cancer Institute, Rotterdam, Netherlands. FAU - Hicking, Christine AU - Hicking C AD - Merck KGaA, Darmstadt, Germany. FAU - Markivskyy, Andriy AU - Markivskyy A AD - Merck KGaA, Darmstadt, Germany. FAU - Picard, Martin AU - Picard M AD - Merck KGaA, Darmstadt, Germany. FAU - Weller, Michael AU - Weller M AD - UniversitatsSpital Zurich, Zurich, Switzerland. CN - European Organisation for Research and Treatment of Cancer (EORTC) CN - Canadian Brain Tumor Consortium CN - CENTRIC study team LA - eng SI - ClinicalTrials.gov/NCT00689221 PT - Clinical Trial, Phase III PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140819 PL - England TA - Lancet Oncol JT - The Lancet. Oncology JID - 100957246 RN - 0 (Snake Venoms) RN - 0 (Tumor Suppressor Proteins) RN - 4EDF46E4GI (Cilengitide) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.1.1.- (DNA Modification Methylases) RN - EC 2.1.1.63 (MGMT protein, human) RN - EC 6.5.1.- (DNA Repair Enzymes) RN - YF1K15M17Y (Temozolomide) SB - IM CIN - Lancet Oncol. 2014 Sep;15(10):1044-5. PMID: 25163907 CIN - Lancet Oncol. 2014 Dec;15(13):e584-5. PMID: 25456376 CIN - Lancet Oncol. 2014 Dec;15(13):e585-6. PMID: 25456377 MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Brain Neoplasms/*drug therapy/genetics/mortality/pathology MH - Confidence Intervals MH - DNA Modification Methylases/*genetics MH - DNA Repair Enzymes/*genetics MH - Dacarbazine/*analogs & derivatives/therapeutic use MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Early Detection of Cancer/methods MH - Female MH - Follow-Up Studies MH - Glioblastoma/*drug therapy/genetics/mortality/pathology MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasm Invasiveness/pathology MH - Neoplasm Staging MH - Patient Selection MH - Promoter Regions, Genetic MH - Proportional Hazards Models MH - Reference Values MH - Snake Venoms/*therapeutic use MH - Survival Analysis MH - Temozolomide MH - Treatment Outcome MH - Tumor Suppressor Proteins/*genetics EDAT- 2014/08/29 06:00 MHDA- 2015/01/15 06:00 CRDT- 2014/08/29 06:00 PHST- 2014/08/29 06:00 [entrez] PHST- 2014/08/29 06:00 [pubmed] PHST- 2015/01/15 06:00 [medline] AID - S1470-2045(14)70379-1 [pii] AID - 10.1016/S1470-2045(14)70379-1 [doi] PST - ppublish SO - Lancet Oncol. 2014 Sep;15(10):1100-8. doi: 10.1016/S1470-2045(14)70379-1. Epub 2014 Aug 19.