PMID- 33230210 OWN - NLM STAT- MEDLINE DCOM- 20210714 LR - 20210714 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 124 IP - 4 DP - 2021 Feb TI - A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. PG - 728-735 LID - 10.1038/s41416-020-01151-6 [doi] 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 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. FAU - van Bussel, Mark T J AU - van Bussel MTJ AUID- ORCID: 0000-0003-0048-6314 AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. m.v.bussel@nki.nl. FAU - Awada, Ahmad AU - Awada A AD - Oncology Medicine Department, Jules Bordet Institute, Universite Libre de Bruxelles, Brussels, Belgium. FAU - de Jonge, Maja J A AU - de Jonge MJA AD - Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. FAU - Mau-Sorensen, Morten AU - Mau-Sorensen M AUID- ORCID: 0000-0003-2235-1250 AD - Department of Oncology, Rigshospitalet, Copenhagen, Denmark. FAU - Nielsen, Dorte AU - Nielsen D AD - Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark. FAU - Schoffski, Patrick AU - Schoffski P AD - Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. FAU - Verheul, Henk M W AU - Verheul HMW AD - Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - Sarholz, Barbara AU - Sarholz B AD - Merck KGaA, Darmstadt, Germany. FAU - Berghoff, Karin AU - Berghoff K AD - Merck KGaA, Darmstadt, Germany. FAU - El Bawab, Samer AU - El Bawab S AD - Merck KGaA, Darmstadt, Germany. FAU - Kuipers, Mirjam AU - Kuipers M AD - Merck KGaA, Darmstadt, Germany. FAU - Damstrup, Lars AU - Damstrup L AD - Merck KGaA, Darmstadt, Germany. AD - Debiopharm International S.A., Lausanne, Switzerland. FAU - Diaz-Padilla, Ivan AU - Diaz-Padilla I AD - Ares Trading S.A., Eysins, Switzerland; an Affiliate of Merck KGaA, Darmstadt, Germany. FAU - Schellens, Jan H M AU - Schellens JHM AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. AD - Synthon Biopharmaceuticals, Nijmegen, The Netherlands. LA - eng SI - ClinicalTrials.gov/NCT02316197 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201124 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridazines) RN - 0 (Quinazolines) RN - EC 2.7.11.1 (DNA-Activated Protein Kinase) RN - GN429E725A (peposertib) SB - IM MH - Adult MH - Aged MH - DNA-Activated Protein Kinase/*antagonists & inhibitors/metabolism MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy/metabolism/pathology MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/pharmacokinetics MH - Pyridazines/*administration & dosage/*adverse effects/pharmacokinetics MH - Quinazolines/*administration & dosage/*adverse effects/pharmacokinetics PMC - PMC7884679 COIS- M.T.J.v.B., M.M.-S. and D.N. declare no potential conflicts of interest. A.A. has undertaken advisory roles and received speaker fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Eli Lilly, Genomic Health, Hoffmann-La Roche, Ipsen, Leo Pharma, Merck & Co., Novartis and Pfizer. M.J.A.d.J. has participated in advisory boards on behalf of Faron Pharmaceuticals. P.S. has received honoraria and has undertaken consultancy work for Deciphera. H.M.W.V. has participated in advisory boards on behalf of Lava Therapeutics and Glycostem, for which fees were paid to his institution. B.S., K.B., S.E.B. and M.K. are employees of Merck KGaA, Darmstadt, Germany. L.D. was an employee of Merck KGaA, Darmstadt, Germany, at the time of study conduct, and is currently an employee of Debiopharm International S.A., Lausanne, Switzerland. I.D.-P. is an employee of Ares Trading S.A., Eysins, Switzerland; an affiliate of Merck KGaA, Darmstadt, Germany. J.H.M.S. is patent holder on development of oral taxanes and shareholder of Modra Pharmaceuticals B.V. EDAT- 2020/11/25 06:00 MHDA- 2021/07/15 06:00 PMCR- 2020/11/24 CRDT- 2020/11/24 06:01 PHST- 2020/06/18 00:00 [received] PHST- 2020/10/22 00:00 [accepted] PHST- 2020/10/07 00:00 [revised] PHST- 2020/11/25 06:00 [pubmed] PHST- 2021/07/15 06:00 [medline] PHST- 2020/11/24 06:01 [entrez] PHST- 2020/11/24 00:00 [pmc-release] AID - 10.1038/s41416-020-01151-6 [pii] AID - 1151 [pii] AID - 10.1038/s41416-020-01151-6 [doi] PST - ppublish SO - Br J Cancer. 2021 Feb;124(4):728-735. doi: 10.1038/s41416-020-01151-6. Epub 2020 Nov 24.