A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours
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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. / 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.
I: British Journal of Cancer, Bind 124, Nr. 4, 16.02.2021, s. 728-735.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours
AU - van Bussel, Mark T.J.
AU - Awada, Ahmad
AU - de Jonge, Maja J.A.
AU - Mau-Sørensen, Morten
AU - Nielsen, Dorte
AU - Schöffski, Patrick
AU - Verheul, Henk M.W.
AU - Sarholz, Barbara
AU - Berghoff, Karin
AU - El Bawab, Samer
AU - Kuipers, Mirjam
AU - Damstrup, Lars
AU - Diaz-Padilla, Ivan
AU - Schellens, Jan H.M.
N1 - Publisher Copyright: © 2020, The Author(s).
PY - 2021/2/16
Y1 - 2021/2/16
N2 - 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. Clinical trial registration: NCT02316197.
AB - 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. Clinical trial registration: NCT02316197.
U2 - 10.1038/s41416-020-01151-6
DO - 10.1038/s41416-020-01151-6
M3 - Journal article
C2 - 33230210
AN - SCOPUS:85096436027
VL - 124
SP - 728
EP - 735
JO - The British journal of cancer. Supplement
JF - The British journal of cancer. Supplement
SN - 0007-0920
IS - 4
ER -
ID: 286306026