{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T03:10:41Z","timestamp":1740107441902,"version":"3.37.3"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Eligible patients were\u2009\u2265\u200918\u00a0years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225\u00a0mg twice daily on days 1\u20132 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (C<jats:sub>max<\/jats:sub>) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Twenty-one patients received adavosertib. Concentration\u2013QT modeling of \u0394QTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of C<jats:sub>max<\/jats:sub> observed on days 1 and 3 were below the threshold for regulatory concern (not\u2009&gt;\u200910\u00a0ms). No significant relationship between \u0394QTcF (vs baseline) and adavosertib concentration was identified (<jats:italic>P<\/jats:italic>\u2009=\u20090.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Adavosertib does not have a clinically important effect on QTc prolongation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>ClinicalTrials.gov<\/jats:title>\n                <jats:p>NCT03333824.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-023-04555-2","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T09:06:09Z","timestamp":1687856769000},"page":"141-150","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study"],"prefix":"10.1007","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-1638","authenticated-orcid":false,"given":"Mats","family":"N\u00e5g\u00e5rd","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-Lin","family":"Ah-See","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Strauss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trisha","family":"Wise-Draper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard P.","family":"Safran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Nadeau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William J.","family":"Edenfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lionel D.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dinko","family":"Reki\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corina","family":"Dota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lone H.","family":"Ottesen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganesh M.","family":"Mugundu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"4555_CR1","doi-asserted-by":"publisher","first-page":"3409","DOI":"10.1200\/jco.2014.60.4009","volume":"33","author":"K Do","year":"2015","unstructured":"Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S (2015) Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. 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He also received, through an award to his institution, clinical trial funding for this study from AstraZeneca and other similar clinical trial funding support from the following sponsors: Bristol Myers Squibb, Bayer Pharmaceuticals, and AbbVie. WJE is a consultant for Chimerix Corp. CD, DR, MA, and MN are employees and shareholders of AstraZeneca. LHO was an employee of AstraZeneca at the time of conduct and reporting of this study. LHO is also a shareholder of AstraZeneca. All other authors have declared no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, applicable local regulatory requirements, and the AstraZeneca policy on bioethics [].","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The institutional review boards or independent ethics committees of all investigational sites approved the protocol, and all patients provided written, informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}]}}