We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
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.
- Authors
Le Tourneau, Christophe; Delord, Jean-Pierre; Kotecki, Nuria; Borcoman, Edith; Gomez-Roca, Carlos; Hescot, Ségolène; Jungels, Christiane; Vincent-Salomon, Anne; Cockenpot, Vincent; Eberst, Lauriane; Molé, Audrey; Jdey, Wael; Bono, Françoise; Trochon-Joseph, Véronique; Toussaint, Hélène; Zandanel, Christelle; Adamiec, Olga; de Beaumont, Olivier; Cassier, Philippe Alexandre
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>The dose of 600 mg was identified as the optimal dose for further clinical development.<bold>Clinical Trial Registration: </bold>Clinical trial registration (NCT number): NCT03579628.
- Publication
British Journal of Cancer, 2020, Vol 123, Issue 10, p1481
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-01028-8