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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


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  • Mark T J van Bussel
  • Ahmad Awada
  • Maja J A de Jonge
  • Morten Mau-Sørensen
  • Dorte Nielsen
  • Patrick Schöffski
  • Henk M W Verheul
  • Barbara Sarholz
  • Karin Berghoff
  • Samer El Bawab
  • Mirjam Kuipers
  • Lars Damstrup
  • Ivan Diaz-Padilla
  • Jan H M Schellens
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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 Tmax 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.


TidsskriftBritish Journal of Cancer
Udgave nummer4
Sider (fra-til)728-735
Antal sider8
StatusUdgivet - feb. 2021

ID: 61374083