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

• Published in: British journal of cancer Vol. 123; no. 10; pp. 1481 - 1489
• Main 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 10.11.2020; Nature Publishing Group UK
• Subjects: Adenosine; Adenosine kinase; Administration, Intravenous; Adult; Aged; Belgium; Cholesterol - administration & dosage; Cholesterol - adverse effects; Cholesterol - analogs & derivatives; Cholesterol - pharmacokinetics; Clinical trials; Deoxyribonucleic acid; Disease Progression; DNA; DNA - administration & dosage; DNA - adverse effects; DNA - pharmacokinetics; DNA damage; DNA repair; DNA Repair - drug effects; DNA-dependent protein kinase; Dose-Response Relationship, Drug; Enzymes; Female; France; Humans; Hypotension; Kinases; Liver; Male; Maximum Tolerated Dose; Middle Aged; Mimicry; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oligonucleotides; Pharmacodynamics; Pharmacokinetics; Phosphorylation; Ribose; Solid tumors; Tumors; Belgium; France
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01028-8

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. 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. 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. The dose of 600 mg was identified as the optimal dose for further clinical development. Clinical trial registration (NCT number): NCT03579628.