Mark T J van Bussel1, Ahmad Awada2, Maja J A de Jonge3, Morten Mau-Sørensen4, Dorte Nielsen5, Patrick Schöffski6, Henk M W Verheul7, Barbara Sarholz8, Karin Berghoff8, Samer El Bawab8, Mirjam Kuipers8, Lars Damstrup8,9, Ivan Diaz-Padilla10, Jan H M Schellens11,12. 1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. m.v.bussel@nki.nl. 2. Oncology Medicine Department, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium. 3. Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 4. Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 5. Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark. 6. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. 7. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 8. Merck KGaA, Darmstadt, Germany. 9. Debiopharm International S.A., Lausanne, Switzerland. 10. Ares Trading S.A., Eysins, Switzerland; an Affiliate of Merck KGaA, Darmstadt, Germany. 11. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 12. Synthon Biopharmaceuticals, Nijmegen, The Netherlands.
Abstract
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.
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.
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