title: A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma.
abstract: OBJECTIVE
  Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma.
  
  
  METHODS
  Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced.
  
  
  RESULTS
  Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1-19.6] for rRT and 20.7% (95% CI, 11.2-33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3-3.8) months and 4.5 (95% CI, 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27-0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36-1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06-0.58) for treatment with APG101, suggesting a potential biomarker.
  
  
  CONCLUSIONS
  CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker.
authors.affiliation: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit-Neurooncology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany. wolfgang.wick@med.uni-heidelberg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Fricke
authors.affiliation: Premier Research Germany Ltd., Darmstadt, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Junge
authors.affiliation: Burdenko Neurosurgery Research Institute, Moscow, Russia.
authors.forename: Grigory
authors.initials: G
authors.lastname: Kobyakov
authors.affiliation: Clinic for Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Martens
authors.affiliation: Clinic for Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Heese
authors.affiliation: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit-Neurooncology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.affiliation: Clinical Cooperation Unit-Neurooncology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Maximilian G
authors.initials: MG
authors.lastname: Schliesser
authors.affiliation: Clinical Cooperation Unit-Neuropathology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany. Institute of Neuropathology, University Clinic Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Internal Medicine and Neurooncology, Landesnervenklinik Linz, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Pichler
authors.affiliation: Burdenko Neurosurgery Research Institute, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Vetlova
authors.affiliation: Department of Neuroradiology, Neurology Clinic and Radiology Clinic, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Harting
authors.affiliation: Department of Radiation Oncology, Radiology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: Clinical Cooperation Unit-Neuropathology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany. Institute of Neuropathology, University Clinic Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Apogenix GmbH, Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kunz
authors.affiliation: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit-Neuroimmunology and Brain Tumour Immunology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of Neuroradiology, Neurology Clinic and Radiology Clinic, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.affiliation: Department of Radiation Oncology, Radiology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011788:Quality of Life; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult; D019014:fas Receptor / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C574675:APG101