L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial

Frank A. Giordano (), Julian P. Layer, Sonia Leonardelli, Lea L. Friker, Roberta Turiello, Dillon Corvino, Thomas Zeyen, Christina Schaub, Wolf Müller, Elena Sperk, Leonard Christopher Schmeel, Katharina Sahm, Christoph Oster, Sied Kebir, Peter Hambsch, Torsten Pietsch, Sotirios Bisdas, Michael Platten, Martin Glas, Clemens Seidel, Ulrich Herrlinger and Michael Hölzel ()
Additional contact information
Frank A. Giordano: Medical Faculty Mannheim, University of Heidelberg
Julian P. Layer: University of Bonn
Sonia Leonardelli: University of Bonn
Lea L. Friker: University of Bonn
Roberta Turiello: University of Bonn
Dillon Corvino: University of Bonn
Thomas Zeyen: University Hospital Bonn
Christina Schaub: University Hospital Bonn
Wolf Müller: University of Leipzig
Elena Sperk: Medical Faculty Mannheim, University of Heidelberg
Leonard Christopher Schmeel: University of Bonn
Katharina Sahm: DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
Christoph Oster: University Duisburg-Essen
Sied Kebir: University Duisburg-Essen
Peter Hambsch: University of Leipzig
Torsten Pietsch: University of Bonn
Sotirios Bisdas: University College London
Michael Platten: DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
Martin Glas: University Duisburg-Essen
Clemens Seidel: University of Leipzig
Ulrich Herrlinger: University Hospital Bonn
Michael Hölzel: University of Bonn

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Date: 2024
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DOI: 10.1038/s41467-024-48416-9

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