Abstract
Abstract BACKGROUND AsiDNA is a synthetic cholesterol-oligodeoxyribonucleotide conjugate, inducing false DNA damage signaling, which prevents DNA repair in tumor cells. AsiDNA therefore increases the vulnerability of tumor cells to irradiation without increasing toxicity in healthy tissues. Preclinical data showed encouraging results of AsiDNA combined to irradiation in glioma and medulloblastoma models. We aimed to determine the safety and efficacy of AsiDNA, a DNA-repair inhibitor, in children, adolescents and young adults with recurrent High-grade Glioma (HGG) eligible for re-irradiation. METHODS AsiDNA was administered intravenously using a 3 consecutive days loading dose, followed by a weekly dose (350 mg/m2/dose or 600 mg for patients ≥ 50kg) for 11 weeks. Focal radiotherapy, using 1.8 Gy daily fraction, 5 days a week, was administered in combination during the first weeks: 18 Gy for brainstem diffuse midline glioma (DMG) and 36 Gy for supra-tentorial HGG (DMG or non-DMG). The first part of the study aimed to assess the safety and to confirm the recommended phase-II dose based on dose limiting toxicities (DLT) during the first 8 weeks. A second part was planned to assess activity/efficacy of the combination based on the progression-free survival (PFS) rate at 3 months. AsiDNA pharmacodynamics (PD) was studied in peripheral blood mononuclear cells (PMBC). RESULTS Eight (8) patients were enrolled: median age 14 y (6.2-24.5), 5 DMG. No DLT was observed. Median FU was 9.1 months, disease progression was observed in 8 patients; 6 died because of disease progression. Median PFS was 3.9 months. The PD results showed no significant target engagement in PBMCs. CONCLUSIONS Considering the low PFS as well as lack of efficacy on PD markers, the DSMB recommended stopping the study.
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