{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:04:51Z","timestamp":1773029091603,"version":"3.50.1"},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Tuvusertib is an investigational, orally administered inhibitor of ATR protein kinase, currently in Phase II clinical development. Here, we present an integrated nonclinical and clinical assessment of the effect of tuvusertib on QTc interval. In\u00a0vitro inhibition by tuvusertib of the hERG potassium channel was evaluated, and in\u00a0vivo ECG assessments evaluated the effect on QTc in dogs. PK\u2010matched triplicate ECGs in patients receiving tuvusertib in Part A1 of the Phase I DDRiver Solid Tumors 301 study (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200955; dosing regimens: 5\u2013270\u2009mg QD, 180\u2013220\u2009mg QD 2\u2009weeks on\/1\u2009week off, or 150\u2009mg BID 4\u2009days on\/3\u2009days off) contributed to concentration\u2010QTc analyses via linear mixed\u2010effects modeling. In\u00a0vitro, tuvusertib inhibited hERG with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 2.83\u2009\u03bcM, which is ~2.5 times its steady\u2010state unbound\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    at the clinical RDE (180\u2009mg QD 2\u2009weeks on\/1\u2009week off). In\u00a0vivo, tuvusertib did not affect QTc up to 5\u2009mg\/kg\/day in dogs (unbound\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    comparable to that at clinical RDE). In patients with advanced solid tumors receiving tuvusertib at up to threefold higher plasma concentrations than at the RDE, the risk for clinically relevant QTc prolongation was assessed to be low (upper limit of 90% CI of model\u2010predicted \u0394QTcF &lt;\u200920\u2009ms). There was no relationship between tuvusertib plasma concentration and RR interval, suggesting no effect on HR. Early integrated concentration\u2010QTc assessments of tuvusertib monotherapy in Phase I were crucial in informing the low risk for clinically relevant QTc prolongation, thereby facilitating efficient evaluation of investigational tuvusertib combination strategies in ongoing clinical development.\n                  <\/jats:p>","DOI":"10.1111\/cts.70496","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T04:23:51Z","timestamp":1770783831000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Integrated Nonclinical and Clinical Risk Assessment of the Effects of Investigational\n                    <scp>ATRi<\/scp>\n                    Tuvusertib on\n                    <scp>QTc<\/scp>\n                    Interval in Patients With Solid Tumors"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7969-9238","authenticated-orcid":false,"given":"Jatinder Kaur","family":"Mukker","sequence":"first","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2154-3309","authenticated-orcid":false,"given":"Timothy A.","family":"Yap","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6322-9721","authenticated-orcid":false,"given":"Anthony W.","family":"Tolcher","sequence":"additional","affiliation":[{"name":"New Experimental Therapeutics (NEXT)  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2034-595X","authenticated-orcid":false,"given":"Johann S.","family":"de Bono","sequence":"additional","affiliation":[{"name":"Royal Marsden Hospital  Sutton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-1444","authenticated-orcid":false,"given":"Ruth","family":"Plummer","sequence":"additional","affiliation":[{"name":"Newcastle University and Northern Centre for Cancer Care, Newcastle Hospitals NHS Trust  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2469-840X","authenticated-orcid":false,"given":"Gary","family":"Grosser","sequence":"additional","affiliation":[{"name":"the healthcare business of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1403-6511","authenticated-orcid":false,"given":"Christoph","family":"van Amsterdam","sequence":"additional","affiliation":[{"name":"the healthcare business of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4497-0516","authenticated-orcid":false,"given":"Hanno","family":"Schieferstein","sequence":"additional","affiliation":[{"name":"the healthcare business of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1596-6062","authenticated-orcid":false,"given":"Han","family":"Witjes","sequence":"additional","affiliation":[{"name":"Certara USA, Inc.  Radnor Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3567-7903","authenticated-orcid":false,"given":"Paul Matthias","family":"Diderichsen","sequence":"additional","affiliation":[{"name":"Certara USA, Inc.  Radnor Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2682-4670","authenticated-orcid":false,"given":"Axel","family":"Krebs\u2010Brown","sequence":"additional","affiliation":[{"name":"the healthcare business of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3149-8486","authenticated-orcid":false,"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-7984","authenticated-orcid":false,"given":"Rainer","family":"Strotmann","sequence":"additional","affiliation":[{"name":"the healthcare business of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8080-3545","authenticated-orcid":false,"given":"Zoltan","family":"Szucs","sequence":"additional","affiliation":[{"name":"Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2755-6597","authenticated-orcid":false,"given":"Ioannis","family":"Gounaris","sequence":"additional","affiliation":[{"name":"Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA  Darmstadt Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4039-9813","authenticated-orcid":false,"given":"Karthik","family":"Venkatakrishnan","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.015"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2017.08.013"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap9346"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2022-2588"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2409"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.3018"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.2612"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.70029"},{"key":"e_1_2_9_10_1","unstructured":"USFDA Center for Drug Evaluation and Research \u201cManual of Policies and Procedures \u201daccessed February 6 2025 https:\/\/www.fda.gov\/media\/183018\/download."},{"key":"e_1_2_9_11_1","unstructured":"European Medicines Agency \u201cICH Topic E14. 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