دورية أكاديمية
A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours
| العنوان: | A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours |
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| المؤلفون: | Burris, Howard A., Berlin, Jordan, Arkenau, Tobias, Cote, Gregory M., Lolkema, Martijn P., Ferrer-Playan, Jordi, Kalapur, Anup, Bolleddula, Jayaprakasam, Locatelli, Giuseppe, Goddemeier, Thomas, Gounaris, Ioannis, de Bono, Johann |
| المصدر: | Burris , H A , Berlin , J , Arkenau , T , Cote , G M , Lolkema , M P , Ferrer-Playan , J , Kalapur , A , Bolleddula , J , Locatelli , G , Goddemeier , T , Gounaris , I & de Bono , J 2024 , ' A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours ' , British Journal of Cancer , vol. 130 , no. 7 , pp. 1131-1140 . https://doi.org/10.1038/s41416-023-02436-2Test |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being |
| الوصف: | Background: 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 ± carboplatin in patients with advanced solid tumours. Methods: 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) Results : Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). 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 mg 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 UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation. Conclusion: Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued. ClinicalTrials.gov: NCT02278250. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://pure.eur.nl/en/publications/b8ce9c63-fcd1-4d75-8a2c-a2e3ab21d904Test |
| DOI: | 10.1038/s41416-023-02436-2 |
| الإتاحة: | https://doi.org/10.1038/s41416-023-02436-2Test https://pure.eur.nl/en/publications/b8ce9c63-fcd1-4d75-8a2c-a2e3ab21d904Test https://pure.eur.nl/ws/files/134687658/A_phase_I_study_of_ATR_inhibitor_gartisertib_M4344_as_a_single_agent_and_in_combination_with_carboplatin_in_patients_with_advanced_solid_tumours.pdfTest http://www.scopus.com/inward/record.url?scp=85183421277&partnerID=8YFLogxKTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.2146C460 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41416-023-02436-2 |
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