Journal Article

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

Friker, Lea L., Hölzel, Michael, Müller, Wolf, Seidel, Clemens, Oster, Christoph, Sahm, Katharina, Hambsch, Peter, Schmeel, Leonard Christopher, Platten, Michael, Corvino, Dillon, Bisdas, Sotirios, Zeyen, Thomas, Leonardelli, Sonia, Kebir, Sied, Turiello, Roberta, Glas, Martin, Herrlinger, Ulrich, Giordano, Frank A., Layer, Julian P., Schaub, Christina, Sperk, Elena, Pietsch, Torsten

2024

Overview

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. Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/63 / 59/57 / 692/308/575 / 692/699/67/1059/485 / 692/699/67/1059/602 / 692/699/67/1922 / 82/1 / 82/51 / 82/80 / Adult / Aged / Aptamers / Aptamers, Nucleotide - administration & dosage / Blood volume / Brain Neoplasms - drug therapy / Brain Neoplasms - radiotherapy / Cerebral blood flow / Chemokine CXCL12 - blood / Chemokines / CXCL12 protein / Effectiveness / Female / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - radiotherapy / Glioma / Glioma cells / Humanities and Social Sciences / Humans / Male / Maximum Tolerated Dose / Methylation / Middle Aged / multidisciplinary / Neoplasm Recurrence, Local / Oncology / Patients / Plasma levels / Quality of Life / Radiation dosage / Radiation therapy / Remission / Safety / Science / Science (multidisciplinary) / Survival / Tumors / Vascularization