{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:44:52Z","timestamp":1747183492884,"version":"3.40.5"},"reference-count":45,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020955","name":"GlaxoSmithKline Biologicals","doi-asserted-by":"publisher","award":["NCT02715284; 215333"],"award-info":[{"award-number":["NCT02715284; 215333"]}],"id":[{"id":"10.13039\/100020955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Patients with solid tumours were treated with the anti\u2010PD\u20101 antibody dostarlimab in the Phase I GARNET trial. This study aimed to examine dostarlimab's effect on corrected QT (QTc) interval and the systemic concentration\u2013QTc interval relationship.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In GARNET Part 2B, patients received 500\u2009mg dostarlimab every 3\u00a0weeks (Q3W) for four cycles, then 1000\u2009mg Q6W. Triplicate 12\u2010lead ECGs were recorded and time\u2010matched pharmacokinetic (PK) samples collected at screening, on Day 1 of Cycles 1, 4, 5, 8, 12 (pre\u2010dose and 0.5\u00a0h after infusion end), and at treatment end. Concentration\u2013change from baseline QTcF (\u0394QTcF) analysis using a linear mixed effects model, summary statistics, incidence of clinically noteworthy ECG values and rhythm abnormalities were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 377 patients were considered for evaluation (<jats:italic>n<\/jats:italic>\u2009=\u200915 excluded from concentration\u2013\u0394QTcF). There was a non\u2010significant concentration\u2013\u0394QTcF relationship (0.001589\u2009ms\/\u03bcg\/mL; <jats:italic>P<\/jats:italic>\u2009=\u2009.5906). Mean \u0394QTcF increase was &lt;6\u00a0ms (upper\u2010bound two\u2010sided 90% confidence interval [CI], &lt;10\u00a0ms at all post\u2010dose timepoints). Highest geometric mean concentration was 414.1\u00a0\u03bcg\/mL (Cycle 5 Day 1, 0.5\u00a0h) with predicted mean \u2206QTcF of 3.064\u2009ms (upper\u2010bound two\u2010sided 90% CI: 5.071). Mean QTcF prolongation (all concentrations) was 2.4\u00a0ms. QTcF prolongation \u2265500\u2009ms occurred in five patients (1.3%); 51 (13.6%) and nine patients (2.4%) had \u0394QTcF \u226530\u2009ms and \u226560\u2009ms, respectively. Ten patients (2.7%) reported rhythm abnormalities. No U\u2010wave abnormalities, torsades de pointes, ventricular tachycardia or ventricular fibrillation\/flutter were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Dostarlimab does not cause clinically significant QTcF prolongation exceeding the regulatory concern threshold.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15700","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T04:28:00Z","timestamp":1677212880000},"page":"2272-2282","source":"Crossref","is-referenced-by-count":1,"title":["Dostarlimab, an anti\u2010programmed death\u20101 monoclonal antibody, does not cause QT prolongation in patients with solid tumours: A concentration\u2010QT analysis"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0349-7756","authenticated-orcid":false,"given":"Mita","family":"Kuchimanchi","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation GSK  Waltham Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Dabrowski","sequence":"additional","affiliation":[{"name":"Global Safety Oncology GSK  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Lu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation GSK  Waltham Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murad","family":"Melhem","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Modeling and Simulation GSK  Waltham Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010019\u201000748\u20102"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030738"},{"key":"e_1_2_10_4_1","unstructured":"FDA.FDA grants accelerated approval to dostarlimab\u2010gxly for dMMR endometrial cancer.https:\/\/www.fda.gov\/drugs\/resources\u2010information\u2010approved\u2010drugs\/fda\u2010grants\u2010accelerated\u2010approval\u2010dostarlimab\u2010gxly\u2010dmmr\u2010endometrial\u2010cancer. 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