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BACKGROUND Preclinical studies showed that CXCL12-mediated influx of highly angiogenic monocytes/macrophages is a key driver of tumor re-vascularization and re-growth after radiotherapy (RT) of glioblastoma (GBM). We report findings from a phase I/II proof-of concept (PoC) study on CXCL12 inhibition during and after RT of GBM. METHODS Patients ≥18years with incompletely or unresected GBM without MGMT promoter hypermethylation and ECOG≤2 were eligible to participate. Patients received continuous (24/7) i.v. infusions of 200mg/week (n=3), 400mg/week (n=3) or 600mg/week (n=3) of the CXCL12 inhibitor olaptesed pegol (OLA) for 26 weeks during and after normo- or hypofractionated RT (60Gy/40.05Gy). The primary endpoint was safety as per the incidence of treatment-related adverse events. The study was accompanied by PoC-research including multiparametric MRI biomarkers (relative cerebral blood volume, rCBV; fractional tumor burden with high perfusion, FTBhigh; apparent diffusion coefficient, ADC) and of multiplexed immunofluorescence imaging (CODEX®) of reference and patient samples. Initial results of these analyses are reported for the first six patients enrolled. RESULTS Five of six (83%) patients assessed with advanced MRI showed response under OLA in rCBV/FTBhigh and ADC. Maximum reduction in perfusion (rCBV) from baseline was 55%, maximum reduction of FTBhigh was 55% and maximum increase in ADC was 77%. Furthermore, five of six (83%) patients analyzed showed reduction of enhancing tissue volumes in at least one scan under OLA therapy. In both one patient and two reference samples CXCL12 co-localized with endothelial cells of the microvascular proliferation zone. In a paired sample (before/during OLA) of one patient, endothelial cells stained positive for CXCL12 before but not during treatment and almost all GBM cells were negative in Ki67 staining in the sample obtained under OLA therapy. CONCLUSIONS Advanced MRI and multiplexed immunofluorescence suggest efficacy of combined radiotherapy and CXCL12 inhibition in unmethylated GBM. Funded by NOXXON Pharma AG; ClinicalTrials.gov number, NCT04121455.

neuro-oncology

CTNI-43. CXCL12 INHIBITION IN MGMT UNMETHYLATED GLIOBLASTOMA – RESULTS OF AN EARLY PROOF-OF-CONCEPT ASSESSMENT IN THE MULTICENTRIC PHASE I/II GLORIA TRIAL (NCT04121455)