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Ataxia telangiectasia mutated (ATM) kinase orchestrates DNA double strand break (DSB) repair; ATM inhibitors may therefore enhance the therapeutic effect of DSB-inducing treatments such as radiotherapy\u00a0(RT). M3541 is an orally administered selective inhibitor of ATM. <jats:italic>Methods.<\/jats:italic> This phase\u00a0I dose-escalation study evaluated the maximum-tolerated dose (MTD), recommended phase II dose(s) (RP2D), safety, pharmacokinetics\u00a0(PK) and antitumor activity of M3541 in combination with fractionated palliative RT in patients with solid tumors. Fifteen patients received palliative RT (30\u00a0Gy in 10 fractions) and escalating doses of M3541 (50\u2013300\u00a0mg administered on RT fraction days) guided by a Bayesian 2-parameter logistic regression model with overdose control. <jats:italic>Results.<\/jats:italic> Doses of M3541 up to 300\u00a0mg\/fraction day were well tolerated. One patient (200\u00a0mg group) experienced two dose-limiting toxicities (urinary tract infection, febrile neutropenia) that resolved with antibiotics. All patients reported\u2009\u2265\u20091\u00a0treatment-emergent adverse event (TEAE) but none led to treatment discontinuation. No grade\u2009\u2265\u20094 TEAEs were reported and there was no indication of a dose effect for any TEAE. Three patients (20.0%; 95% confidence interval 4.3\u201348.1) had confirmed complete or partial response. M3541 total plasma levels did not increase with dose following single or repeated dosing. No relationship was observed between dose and changes in the ratio of phosphorylated to total ATM or in immune cell counts. <jats:italic>Conclusions.<\/jats:italic> The MTD and RP2D could not be established as the study closed early due to the absence of a dose\u2013response relationship and non-optimal PK profile. No further clinical development of M3541 was pursued. (<jats:italic>Trial registration number<\/jats:italic> ClinicalTrials.gov NCT03225105. 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All patients signed an Informed Consent Form before participating in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The Informed Consent Form signed by all patients included the following statement: \u2018At the end of this study, the results may be published or presented. Nothing that could reveal your identity will be included in the publication or presentation.\u2019","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All patients signed an Informed Consent Form before participating in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"This study was conducted in accordance with the ethical principles of the International Council for Harmonisation guideline for Good Clinical Practice and the Declaration of Helsinki, as well as with applicable local regulations. The Clinical Study Protocol and all required associated documents were approved by the following responsible Institutional Review Boards (IRB) or Independent Ethics Committees of the individual study sites: The Western IRB, Indiana University IRB, The Washington University in St. Louis IRB, Vanderbilt University IRB, Henry Ford Health System, Greenville Health System IRB, Chesapeake IRB, Quorum Review IRB, Houston Methodist Cancer Center IRB and Christiana Care Health Services Inc. Local IRB.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants and\/or animals"}},{"value":"SW reports grants or contracts from the SWOG-Clinical Trials Partnership; honoraria from the American Society for Clinical Oncology (ASCO); and participation on a data safety monitoring board for the Hoosier Cancer Research Network. CR reports consulting fees from Varian, Radialogica, AstraZeneca, and EMD Serono. AJO reports grants or contracts from Adaptimmune, Alkermes, Astellas Pharma, Boston Biomedical, Bristol-Myers Squibb, Checkmate Pharmaceuticals, EMD Serono, GlaxoSmithKline, GlycoNex, Immunocore, Incyte, Intensity Therapeutics, Kadmon, Kartos Therapeutics, Kura Oncology, Nektar, NGM Biopharmaceuticals, Oncoceutics, OncoSec, Seattle Genetics, Sound Biologics, Spring Bank, Takeda, and Targovax; and consulting fees from Array BioPharma, Bristol-Myers Squibb, Merck KGaA, Darmstadt, Germany, Sanofi, Pfizer, and Eisai. AS reports grants or contracts from Bristol-Myers Squibb, Mirati, Amgen, Novartis, Merck & Co, AstraZeneca, Sanofi, Abbvie, Cytomx, Macrogenics, Pfizer; and consulting fees from Mirati, Amgen, Sanofi, AstraZeneca, Merck & Co, and Bristol-Myers Squibb. MH reports no competing interests. JB reports grants or contracts to his institution from Novartis, Immunomedics, Bayer, AbbVie(Pharmacyclics), Array, Karyopharm, Lilly, Incyte, Immunomedics, Boston Biomedical, Pfizer, Symphogen, FivePrime, EMD Serono, Macrogenics, I-Mab, Dragonfly, PsiOxus; has participated in Advisory Boards for EMD Serono, AstraZeneca, Ipsen, QED, Clovis, LSK, Seattle Genetics, Bayer, Mirati, and Eisai; and has participated on data and safety monitoring boards for AstraZeneca, the Pancreatic Cancer Action Network, and Novocure. LL is an employee of Merck S.L.U., Mollet del Valles, Spain, an affiliate of Merck KGaA, Darmstadt, Germany. LS, HJ, UH, MG and AS-K are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. DC was an employee of the healthcare business of Merck KGaA, Darmstadt, Germany at the time of the study. This author is no longer an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. Current address: DMC Biopharma Sheffield, United Kingdom. ID-P was an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, at the time of the study. This author is no longer an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. Current address: GlaxoSmithKline, Zug, Switzerland.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}}]}}