{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T02:08:55Z","timestamp":1790215735178,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T00:00:00Z","timestamp":1520380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA21765"],"award-info":[{"award-number":["P30 CA21765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Progressive\/recurrent high\u2010grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a phase 1 study (rolling\u2010six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet\u2010derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c\u2010Met inhibitor, in such patients. Pharmacokinetics of both agents were performed. Biomarkers of cellular pathway activation in peripheral\u2010blood mononuclear cells (PBMC) were evaluated before and after administration of dasatinib. <jats:italic>PDGFRA<\/jats:italic> and <jats:italic>MET<\/jats:italic> amplification, and <jats:italic>PDGFRA<\/jats:italic> mutations were studied in tumor samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010five patients were enrolled in this study (median age: 11.9 years). Eleven patients had DIPG. Glioblastoma accounted for 40% of cases. Dasatinib at 50\u00a0mg\/m<jats:sup>2<\/jats:sup> and crizotinib at 130\u00a0mg\/m<jats:sup>2<\/jats:sup> or 100\u00a0mg\/m<jats:sup>2<\/jats:sup> were poorly tolerated when administered twice daily. Drug administration was then switched to once daily. Dasatinib administered at 50\u00a0mg\/m<jats:sup>2<\/jats:sup> and crizotinib at 215\u00a0mg\/m<jats:sup>2<\/jats:sup> once daily was the MTD. Dose\u2010limiting toxicities consisted of diarrhea, fatigue, proteinuria, hyponatremia, rash, and grade 4 neutropenia. Only two patients received therapy for at least 6 months. No objective radiologic responses were observed. Pharmacokinetics of dasatinib and crizotinib were comparable to previous studies. A statistically significant decrease in the ratio of p\u2010AKT\/total AKT in PBMC occurred after dasatinib administration. <jats:italic>PDGFRA<\/jats:italic> and <jats:italic>MET<\/jats:italic> amplification were found in four and two cases, respectively. Only one of 10 tumors harbored a <jats:italic>PDGFRA<\/jats:italic> mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This drug combination was poorly tolerated and its activity was minimal. We do not recommend further testing of this combination in children.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.27035","type":"journal-article","created":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T10:22:42Z","timestamp":1520418162000},"source":"Crossref","is-referenced-by-count":49,"title":["Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high\u2010grade and diffuse intrinsic pontine glioma"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-0463","authenticated-orcid":false,"given":"Alberto","family":"Broniscer","sequence":"first","affiliation":[{"name":"Department of Oncology St. Jude Children's Research Hospital  Memphis Tennessee"},{"name":"Department of Pediatrics University of Tennessee Health Science Center  Memphis 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Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arzu","family":"Onar\u2010Thomas","sequence":"additional","affiliation":[{"name":"Department of Biostatistics St. Jude Children's Research Hospital  Memphis Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar","family":"Gajjar","sequence":"additional","affiliation":[{"name":"Department of Oncology St. Jude Children's Research Hospital  Memphis Tennessee"},{"name":"Department of Pediatrics University of Tennessee Health Science Center  Memphis Tennesssee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana C.","family":"Raimondi","sequence":"additional","affiliation":[{"name":"Department of Pathology St. Jude Children's Research Hospital  Memphis Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth G.","family":"Tatevossian","sequence":"additional","affiliation":[{"name":"Department of Pathology St. Jude Children's Research Hospital  Memphis Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clinton F.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis 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