{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T23:10:50Z","timestamp":1793661050353,"version":"4.5.1"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Br J Cancer"],"published-print":{"date-parts":[[2024,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib\u2009\u00b1\u2009carboplatin in patients with advanced solid tumours.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD\/BID); B1 (DE+carboplatin); and C (biomarker-selected patients).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Overall, 97 patients were enroled into cohorts A (<jats:italic>n<\/jats:italic>\u2009=\u200942), A2 (<jats:italic>n<\/jats:italic>\u2009=\u200926), B1 (<jats:italic>n<\/jats:italic>\u2009=\u200916) and C (<jats:italic>n<\/jats:italic>\u2009=\u200913). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250\u2009mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit <jats:italic>UGT1A1<\/jats:italic>-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (<jats:italic>n<\/jats:italic>\u2009=\u20091 [cohort B1]) and stable disease &gt;6 months (<jats:italic>n<\/jats:italic>\u2009=\u20093) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>ClinicalTrials.gov<\/jats:title>\n                <jats:p>NCT02278250.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41416-023-02436-2","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T09:02:45Z","timestamp":1706518965000},"page":"1131-1140","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours"],"prefix":"10.1038","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1501-2931","authenticated-orcid":false,"given":"Howard A.","family":"Burris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Berlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Arkenau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Cote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn P.","family":"Lolkema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Ferrer-Playan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anup","family":"Kalapur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayaprakasam","family":"Bolleddula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Locatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Goddemeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Gounaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"de Bono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"2436_CR1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ctrv.2017.08.013","volume":"60","author":"L Carrassa","year":"2017","unstructured":"Carrassa L, Damia G. 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JB: grants or contracts to institution from Bayer, AbbVie (Pharmacyclics), Novartis (Array), Karyopharm, Lilly, Incyte, Immunomedics, Boston Biomedical, Pfizer, Symphogen, FivePrime, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, I-Mab, Dragonfly, PsiOxus, Transcenta Therapeutics, Sumitomo Dainippon Pharma Oncology, 23 and me, Atreca, Astellas, BMS, and Tyra; has participated in advisory boards for EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Ipsen, QED, Clovis, Bayer, Mirati, and Eisai, Oxford Biotherapeutics, Biosapiens, Insmed, Boehringer Ingelheim, Merus; and has participated on data and safety monitoring boards for Astra Zeneca, and Novocure. TA: received institutional study grants from Astra Zeneca, Roche, Lilly, Bayer, GSK, Amgen, and Pfizer. GMC: support paid to his institution for the conduct of clinical trials from Servier Pharmaceuticals; advisory board fees and support paid to his institution for the conduct of clinical trials from Epizyme; advisory board fees, compound, and support paid to his institution for the conduct of clinical trials PharmaMar; support paid to his institution for the conduct of clinical trials from Macrogenics; advisory board fees, compound, and support paid to his institution for the conduct of clinical trials from Eisai; compound and support paid to his institution for the conduct of clinical trials from Merck\/EMD Serono Research and Development Institute, an affiliate of Merck KGaA; support paid to his institution for the conduct of clinical trials from Bavarian-Nordic; compound for preclinical research and support paid to his institution for the conduct of clinical trials from Bayer; support paid to his institution for the conduct of clinical trials from SpringWorks Therapeutics; support paid to his institution for the conduct of clinical trials from Repare Therapeutics; advisory board fees and support paid to his institution for the conduct of clinical trials from Foghorn; support paid to his institution for the conduct of clinical trials from SMP Oncology; compound and support paid to his institution for the conduct of clinical trials from Jazz Pharmaceuticals; support paid to his institution for the conduct of clinical trials from RAIN Therapeutics; support paid to his institution for the conduct of clinical trials from BioAtla; support paid to his institution for the conduct of clinical trials from Inhibrx; advisory board fees and support paid to his institution for the conduct of clinical trials from Ikena; advisory board fees and support paid to his institution for the conduct of clinical trials from C4 Therapeutics; advisory board fees from Daiichi Sankyo, Inc. MPL: is an employee of Amgen Inc., Thousand Oaks, CA, USA and has previously received institutional research funding from Sanofi, Johnson and Johnson, MSD, and Astellas and has received consulting fees from Incyte, Amgen, Janssen Cilag B.V., Bayer, Servier, Roche, Pfizer, Sanofi Aventis Netherlands BV and Astellas. JF-P is an employee of Ares Trading SA., Eysins, Switzerland, an affiliate of Merck KGaA. AK and TG are employees of Merck Healthcare KGaA, Darmstadt, Germany. JB is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. GL is an employee of Merck Healthcare KGaA, Darmstadt, Germany. IG is an employee of Merck Serono Ltd., Feltham, UK, an affiliate of Merck KGaA, and holds stocks\/shares in Novartis and Alcon. JdB: Advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, MSD, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo and Vertex Pharmaceuticals; has received research grants from Bayer, Cellcentric, Daiichi, Genentech Roche, GSK, Harpoon Janssen, MSD, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; has held a principal investigator role for Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GSK, Harpoon Janssen, Menarini Silicon Biosystems, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, MSD, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo and Vertex Pharmaceuticals and has received product samples from Daiichi, Bayer, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech Roche, Sanofi Aventis and GSK.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was performed in compliance with the International Council for Harmonisation Good Clinical Practice guideline and in accordance with the Declaration of Helsinki. The study protocol and other relevant documents were reviewed and approved by an Institutional Review Board\/Independent Ethics Committee before study start and all patients provided their written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}