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
| Autor: | Christiane Jungels, Véronique Trochon-Joseph, Carlos Gomez-Roca, Jean-Pierre Delord, Anne Vincent-Salomon, Nuria Kotecki, Olga Adamiec, Wael Jdey, Philippe A. Cassier, Christophe Le Tourneau, Christelle Zandanel, Edith Borcoman, Hélène Toussaint, Audrey Mole, Lauriane Eberst, Vincent Cockenpot, Ségolène Hescot, Olivier de Beaumont, Françoise Bono |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Agonist Cancer Research DNA Repair Maximum Tolerated Dose DNA damage DNA repair medicine.drug_class Pharmacology Article 03 medical and health sciences chemistry.chemical_compound Targeted therapies 0302 clinical medicine Belgium Pharmacokinetics Neoplasms Humans Medicine Protein kinase A Aged 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug business.industry DNA Middle Aged Clinical trial Adenosine diphosphate Cholesterol Oncology chemistry 030220 oncology & carcinogenesis Pharmacodynamics Disease Progression Administration Intravenous Female France business |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/s41416-020-01028-8 |
| Popis: | BackgroundAsiDNA, 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.MethodsThe 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.ResultsThe 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.ConclusionThe dose of 600 mg was identified as the optimal dose for further clinical development.Clinical trial registrationClinical trial registration (NCT number): NCT03579628. |
| Databáze: | OpenAIRE |
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