A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

Abstract

Background AsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation. Methods The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design. Results The MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies. Conclusion The dose of 600 mg was identified as the optimal dose for further clinical development. Clinical trial registration Clinical trial registration (NCT number): NCT03579628.

The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest

“…These observations are further supported by in vitro data, revealing no additional toxicity after continuous or cycling treatment of AsiDNA™ on normal cell models, while simultaneously increasing tumour cell sensitivity with no acquired resistance ( 7 , 8 , 18 ). In addition, human clinical trials have failed to show any dose-limiting toxicity, with none reaching the maximum-tolerated dose ( 19 , 20 ). Recently, AsiDNA™ treatment in combination with carboplatin +/- paclitaxel was tested in patients bearing solid tumours ( 21 ).…”