Abstract A076: Phase I dose escalation study evaluating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AsiDNA, a first-in-class DNA Repair Inhibitor, administered intravenously (IV) in patients with advanced solid tumors
Authors: Tourneau Christophe Le , Delord Jean-Pierre , Cassier Philippe , Kotecki Nuria , Borcoman Edith , Hescot Ségolène , Jungels Christiane , Mole Audrey , Toussaint Hélène , Adamiec Olga , Beaumont Olivier de 
Published: March 2020

Abstract
Background: AsiDNA is a first-in-class oligonucleotide that mimics double-stranded DNA breaks and acts as a decoy to disrupt the DNA damage response at the “real” sites of DNA damage. It also activates the DNA-PK and PARP enzymes that induce the phosphorylation of H2AX and HSP90 and proteins parylation, respectively. As a result, repair enzymes are no longer recruited to the damage sites, ultimately leading to tumor cell death. Importantly, healthy cells, which display proficient cell cycle control, halt their cell division until AsiDNA is depleted. Patients and Methods: The primary objective was to establish dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of IV AsiDNA. Other objectives included the safety profile, PK/PD and preliminary efficacy data. Six dose levels (DLs) were planned: 200, 400, 600, 900, 1300 and 1800 mg. All patients (pts) received a loading dose of AsiDNA for 3 consecutive days (D), followed by a 1 hour IV infusion once a week in 21 days cycles (C). In each subsequent cycle, AsiDNA was given weekly. AsiDNA was administered until disease progression, unacceptable toxicity or patient’s decision. Results: Twenty-two pts were treated in the first 5 DLs (153 infusions). Two DLTs were reported (hepatic enzyme increased Gr 3 and Gr 4 at DL 1300 and DL 900, respectively). One related SAE at D42 (Gr 3 orthostatic hypotension) and one related AE at D28 (Gr 3 hypophosphatemia) both at DL 900. AsiDNA PK increased proportionally and consistently with dose from DL1 to DL5. Baseline and on-treatment biopsies were available for 10 pts. There was a robust activation of DNA-PK evidenced by a significant post-treatment increase of γH2AX and pHSP90 from DL 400 with a maximum at DL 600. The quantification of Ki67 showed a clear decrease of the tumor proliferation rate in 7 out of 10 pts evaluated. Best overall response was disease stabilization in 2 pts (9%) with colorectal cancer at DL 600. Conclusions: AsiDNA IV-MTD was not reached. Biological activity was evidenced by the increase of γH2AX and pHSP90. The favorable safety profile was confirmed. DL 600 has been identified as the optimal biological dose for further development given the favorable safety and PK profiles, robust target engagement, and disease stabilization in 2 pts.
Citation Format: Christophe Le Tourneau, Jean-Pierre Delord, Philippe Cassier, Nuria Kotecki, Edith Borcoman, Ségolène Hescot, Christiane Jungels, Audrey Mole, Hélène Toussaint, Olga Adamiec, Olivier de Beaumont. Phase I dose escalation study evaluating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AsiDNA, a first-in-class DNA Repair Inhibitor, administered intravenously (IV) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A076. doi:10.1158/1535-7163.TARG-19-A076