title: A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma.
abstract: OBJECTIVE
  A randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma.
  
  
  METHODS
  149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400mg weekly added to standard radiochemotherapy followed by 400mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points.
  
  
  RESULTS
  142 patients were evaluated for efficacy (per protocol cohort). 12 moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n=81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55-1.37), for patients without residual tumour (n=61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57-1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52-1.57; P=0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41-1.44; P=0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35-1.67; P=0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27-1.64; P=0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated.
  
  
  CONCLUSIONS
  This study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.
authors.affiliation: Department of Neurosurgery, University Hospital Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: westphal@uke.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Department of Neurosurgery, University Hospital Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Electronic address: oliver.heese@helios-kliniken.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Heese
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Electronic address: joachim.steinbach@med.uni-frankfurt.de.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Department of Neurosurgery, Ludwig Maximilian University München-Grosshadern, Marchioninistrasse 15, 81377 München, Germany. Electronic address: oliver.schnell@med.uni-muenchen.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schnell
authors.affiliation: Department of Neurosurgery, Carus University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. Electronic address: gabriele.schackert@uniklinikum-dresden.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.affiliation: Department of Neurosurgery, Christian Albrecht Universität Kiel, Schittenhelmstrasse 10, 24106 Kiel, Germany. Electronic address: maximilian.mehdorn@uksh.de.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mehdorn
authors.affiliation: Department of Neurosurgery, Justus Liebig University Giessen, Klinikstrasse 33, 35392 Gießen, Germany. Electronic address: dirk.schulz@neuro.med.uni-giessen.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schulz
authors.affiliation: Department of Neurosurgery, University Hospital Bonn, Sigmund-Freud Strasse 25, 53105 Bonn, Germany. Electronic address: matthias.simon@ukb.uni-bonn.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Neurology, Ruhr Universität Bochum, In der Schornau 23-25, 44892 Bochum, Germany. Electronic address: uwe.schlegel@kk-bochum.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlegel
authors.affiliation: Department of Neurosurgery, University Hospital Frankfurt, Schleusenweg 2-16 (Haus 95), 60528 Frankfurt am Main, Germany. Electronic address: c.senft@med.uni-frankfurt.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.affiliation: Department of Neurosurgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Electronic address: karsten.geletneky@med.uni-heidelberg.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Geletneky
authors.affiliation: Department of Neurology, University Hospital Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany. Electronic address: christian.braun@medizin.uni-tuebingen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Braun
authors.affiliation: Universität Dortmund, Fachbereich Statistik, 44221 Dortmund, Germany. Electronic address: jghartung@aol.com.
authors.forename: Joachim G
authors.initials: JG
authors.lastname: Hartung
authors.affiliation: Oncoscience AG, Wedel, Hafenstrasse 32, 22880 Wedel, Germany. Electronic address: d.reuter@oncoscience-ag.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reuter
authors.affiliation: Department of Neuroradiology, University Hospital Würzburg, Josef-Schneiderstrasse 11, 97080 Würzburg, Germany. Electronic address: warmuth-metz@neuroradiologie.uni-wuerzburg.de.
authors.forename: Monika Warmuth
authors.initials: MW
authors.lastname: Metz
authors.affiliation: Oncoscience AG, Wedel, Hafenstrasse 32, 22880 Wedel, Germany. Electronic address: f.bach@oncoscience-ag.de.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Bach
authors.affiliation: Institute for Neuropathology, University Hospital Bonn, Sigmund-Freud Strasse 25, 53105 Bonn, Germany. Electronic address: t-pietsch@uni-bonn.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000523:psychology; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000523:psychology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D025521:Tumor Suppressor Proteins; C501466:nimotuzumab; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D066246:ErbB Receptors; D045643:DNA Repair Enzymes
keywords: Epidermal growth factor receptor; Glioblastoma; Immunotherapy