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

Author

Listed:
  • Frank A. Giordano

    (Medical Faculty Mannheim, University of Heidelberg
    DKFZ-Hector Cancer Institute at the University Medical Center Mannheim)

  • Julian P. Layer

    (University of Bonn
    University of Bonn)

  • Sonia Leonardelli

    (University of Bonn)

  • Lea L. Friker

    (University of Bonn
    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
    Heidelberg University
    German Cancer Research Center)

  • 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
    Heidelberg University
    German Cancer Research Center)

  • Martin Glas

    (University Duisburg-Essen)

  • Clemens Seidel

    (University of Leipzig)

  • Ulrich Herrlinger

    (University Hospital Bonn)

  • Michael Hölzel

    (University of Bonn)

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.

Suggested Citation

  • 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 , 2024. "L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48416-9
    DOI: 10.1038/s41467-024-48416-9
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