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<p>Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking <i>MGMT</i> promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTB<sup>high</sup>) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (<i>p</i> = 0.009; <i>p</i> = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Frank A. Giordano,
  • Julian P. Layer,
  • Roberta Turiello,
  • Lea L. Friker,
  • Oriol Mirallas,
  • Barbara E. F. Pregler,
  • Anna-Laura Potthoff,
  • Thomas Zeyen,
  • Johannes Weller,
  • Elena Sperk,
  • Katharina Sahm,
  • Christoph Oster,
  • Sied Kebir,
  • Peter Hambsch,
  • Niklas Schäfer,
  • Sebastian Kadzik,
  • Mirjam Renovanz,
  • Torsten Pietsch,
  • Sotirios Bisdas,
  • Juan Manuel Sepúlveda-Sánchez,
  • Diego Gómez-Puerto,
  • Maria Vieito,
  • Michael Platten,
  • Eleni Gkika,
  • Oliver M. Grauer,
  • Ghazaleh Tabatabai,
  • Matthias Schneider,
  • Martin Glas,
  • Clemens Seidel,
  • Ulrich Herrlinger,
  • Michael Hölzel

摘要

Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.