A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours

• Published in: British journal of cancer Vol. 124; no. 4; pp. 728 - 735
• Main Authors: van Bussel, Mark T. J., Awada, Ahmad, de Jonge, Maja J. A., Mau-Sørensen, Morten, Nielsen, Dorte, Schöffski, Patrick, Verheul, Henk M. W., Sarholz, Barbara, Berghoff, Karin, El Bawab, Samer, Kuipers, Mirjam, Damstrup, Lars, Diaz-Padilla, Ivan, Schellens, Jan H. M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2021; Nature Publishing Group
• Subjects: 692/308/2779/109/1940; 692/4028/67/1059/153; Adverse events; Biomedical and Life Sciences; Biomedicine; Cancer Research; Deoxyribonucleic acid; DNA; DNA-dependent protein kinase; Drug Resistance; Enzyme inhibitors; Epidemiology; Fever; Kinases; Leukocytes (mononuclear); Molecular Medicine; Nausea; Oncology; Peripheral blood mononuclear cells; Pharmacodynamics; Pharmacokinetics; Protein kinase inhibitors; Solid tumors; T-DNA; Toxicity; Tumors; Vomiting
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01151-6

Background This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Methods Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles. Results Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median T max 1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Conclusions Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. Clinical trial registration NCT02316197