title: 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.
abstract: BACKGROUND
  Cilengitide is a selective αvβ3 and αvβ5 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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Merck KGaA, Darmstadt, Germany.
authors.affiliation: UniversitätsSpital Zürich, Zurich, Switzerland; Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Electronic address: roger.stupp@usz.ch.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.affiliation: Edinburgh Cancer Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Erridge
authors.affiliation: Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Perry
authors.affiliation: The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea.
authors.forename: Yong-Kil
authors.initials: YK
authors.lastname: Hong
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lhermitte
authors.affiliation: Department of Neuropathology, Universität Bonn, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Clinic for Neurosurgery, Clinical Center Serbia and Medical Faculty University of Belgrade, Belgrade, Serbia.
authors.forename: Danica
authors.initials: D
authors.lastname: Grujicic
authors.affiliation: Klinikum der J W Goethe Universität Frankfurt, Frankfurt, Germany.
authors.forename: Joachim Peter
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Heidelberg University Medical Center & German Cancer Research Center, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, Gliwice, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Tarnawski
authors.affiliation: Samsung Medical Center, Sungkyunkwan Univ School of Medicine, Seoul, South Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.affiliation: Universitätsklinikum Freiburg, Freiburg, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.affiliation: Medical Center Haaglanden, The Hague, Netherlands.
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.affiliation: Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Chiung-Chyi
authors.initials: CC
authors.lastname: Shen
authors.affiliation: Bangalore Institute of Oncology, Bangalore, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Rao
authors.affiliation: Szegedi Tudományegyetem, Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Thurzo
authors.affiliation: Department of Neuropathology, Universität Bonn, Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Herrlinger
authors.affiliation: Tata Memorial Centre, Navi Mumbai, India.
authors.forename: Tejpal
authors.initials: T
authors.lastname: Gupta
authors.affiliation: Universitätsklinikum Leipzig, Leipzig, Germany.
authors.forename: Rolf-Dieter
authors.initials: RD
authors.lastname: Kortmann
authors.affiliation: Greater Poland Cancer Centre, Poznań, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Adamska
authors.affiliation: The Christie NHS FT, Manchester, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: McBain
authors.affiliation: Bellaria-Maggiore Hospital, AUSL-IRCCS Institute of Neurological Sciences-Bologna, Italy.
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.affiliation: Klinikum der Universität München, München, Germany.
authors.forename: Joerg Christian
authors.initials: JC
authors.lastname: Tonn
authors.affiliation: Klinikum der Universität München, München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schnell
authors.affiliation: University Hospital Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiegel
authors.affiliation: Seoul National University Bundang Hospital, SNU College of Medicine, Seoul, South Korea.
authors.forename: Chae-Yong
authors.initials: CY
authors.lastname: Kim
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Louis Burt
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Erasmus MC-Cancer Institute, Rotterdam, Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hicking
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Andriy
authors.initials: A
authors.lastname: Markivskyy
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Picard
authors.affiliation: UniversitätsSpital Zürich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012016:Reference Values; D012910:Snake Venoms / Q000627:therapeutic use*; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D012910:Snake Venoms; D025521:Tumor Suppressor Proteins; C422910:Cilengitide; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide