Final results of APG101_CD_002: APG101 plus reirradiation versus reirradiation in the treatment of patients with progressive glioblastoma.
Central Nervous System Tumors
Central Nervous System Tumors
2014 ASCO Annual Meeting
J Clin Oncol 32:5s, 2014 (suppl; abstr 2006^)
2014 ASCO Annual Meeting!
Session: Central Nervous System Tumors
Type: Oral Abstract Session
Time: Sunday June 1, 8:00 AM to 11:00 AM
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Author(s): Michael Platten, Harald Fricke, Klaus Junge, Grigory Kobyakov, Tobias Martens, Oliver Heese, Benedikt Wiestler, Maximilian G Schliesser, Andreas von Deimling, Josef Pichler, Elena Vetlova, Inga Harting, Juergen Debus, Christian Hartmann, Claudia Kunz, Martin Bendszus, Stephanie E. Combs, Wolfgang Wick; Neurooncology, University of Heidelberg Medical Center, Heidelberg, Germany; Apogenix GmbH, Heidelberg, Germany; Premier Research, Darmstadt, Germany; N. N. Burdenko Neurosurgical Institute, Moscow, Russia; University of Hamburg, Hamburg, Germany; Univeritätsklinkum Hamburg-Eppendorf, Hamburg, Germany; CCU Neurooncology, DKFZ, Heidelberg, Germany; Institute of Pathology, Dept Neuropathology, University of Heidelberg, INF 224, and CCU Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany; Landesnervenklinik Linz, Linz, Austria; NSI, Moscow, Russia; Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany; University Hospital Heidelberg, Heidelberg, Germany; Department of Neuropathology, Institute of Pathology, Medizinische Hochschule, Hannover, Germany; Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany
Background: Preclinical data indicate antiinvasive activity of APG101, a CD95-ligand (CD95L)-binding fusion protein, and synergistic activity with radiotherapy in glioblastoma. In healthy volunteers, single doses of up to 20 mg/kg APG101 are safe. Methods: Patients (N=91) with progressive glioblastoma after standard radiochemotherapy (± 1 second-line chemotherapy), provided a tumour diameter of 1-4 cm and time since the end of radiotherapy ≥ 8 months, were randomised 1:2 stratified for tumour diameters ≤ or > 2.5 cm between radiotherapy (36 Gy; 5 times 2 Gy per week; rRT) or rRT+APG101 (400 mg weekly i.v.) to be continued until progression. CD95L was evaluated in tumour tissue. This open-label, non-comparative phase II trial (NCT01071837) sought to demonstrate a doubling in the 6-months progression-free survival (PFS-6) rate with rRT+APG101 assuming a 15% PFS-6 rate with rRT alone. The control arm with rRT alone was added to calibrate for the PFS-6 assumption. Results: Patient characteristics in the intention-to-treat population [N=84 (26 patients rRT, 58 patients rRT + APG101)] were balanced. The PFS-6 rates were 3.8% (95%-CI: 0.1 - 19.6) rRT and 20.7% (95%-CI: 11.2 - 33.4) for rRT+APG101 (p=0.04). 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). Cox regression analysis adjusted for tumour size revealed a HR for rRT+APG101 for death of any cause of 0.60 (95% CI: 0.36-1.01)] (p=0.0559). Patients with lower methylation levels at CpG2 in the CD95L promoter in the tumour tissue had a stronger risk reduction (HR=0.13 95% CI: 0.03-0.52) when treated with APG101. 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 tumour may be developed as a biomarker. Clinical trial information: NCT01071837.
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