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Clin Cancer Res. 2014 Dec 15;20(24):6304-13. doi: 10.1158/1078-0432.CCR-14-0951-T. Epub 2014 Oct 22.

A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma.

Author information

1
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.
2
Apogenix GmbH, Heidelberg, Germany.
3
Premier Research Germany Ltd., Darmstadt, Germany.
4
Burdenko Neurosurgery Research Institute, Moscow, Russia.
5
Clinic for Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
6
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.
7
Clinical Cooperation Unit-Neurooncology, German Consortium of Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany.
8
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.
9
Department of Internal Medicine and Neurooncology, Landesnervenklinik Linz, Austria.
10
Department of Neuroradiology, Neurology Clinic and Radiology Clinic, University Hospital Heidelberg, Heidelberg, Germany.
11
Department of Radiation Oncology, Radiology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
12
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.

Abstract

PURPOSE:

Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma.

EXPERIMENTAL DESIGN:

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.

PMID:
25338498
DOI:
10.1158/1078-0432.CCR-14-0951-T
[Indexed for MEDLINE]
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