{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:20:36Z","timestamp":1793226036484,"version":"4.5.0"},"reference-count":21,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"am","delay-in-days":365,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["UM1 CA228823"],"award-info":[{"award-number":["UM1 CA228823"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["ZIC SC 006743"],"award-info":[{"award-number":["ZIC SC 006743"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA015083"],"award-info":[{"award-number":["P30 CA015083"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose\/recommended phase 2 dose (MTD\/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28\u2010day cycle. PK and PD studies were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010one eligible patients\u2019 median (range) age was 14\u00a0years (6\u201020). Six subjects were treated at 3\u00a0mg\/m<jats:sup>2<\/jats:sup>dose level and 15 were treated in 4\u00a0mg\/m<jats:sup>2<\/jats:sup>dose level. The study included patients with CNS tumors (n\u00a0=\u00a012), sarcomas (n\u00a0=\u00a06), or other solid tumors (n\u00a0=\u00a03). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose\u2010limiting toxicity (DLT) was observed at either dose level. A three\u2010fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4\u00a0mg\/m<jats:sup>2<\/jats:sup>orally administered once weekly.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.28892","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T11:49:39Z","timestamp":1610711379000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase\u2010Clinical Trial Network (PEP\u2010CTN)"],"prefix":"10.1002","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3793-9340","authenticated-orcid":false,"given":"Andrew","family":"Bukowinski","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology Oncology Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bill","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology Oncology Oregon Health and Science University Portland Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel M.","family":"Reid","sequence":"additional","affiliation":[{"name":"Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Liu","sequence":"additional","affiliation":[{"name":"Children's Oncology Group Operation Center Monrovia California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles G.","family":"Minard","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research Baylor College of Medicine Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane B.","family":"Trepel","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Developmental Therapeutics Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Oncology St Jude Children's Research Hospital Memphis Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda J.","family":"Weigel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Minnesota Masonic Cancer Center Minneapolis Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.22.1291"},{"key":"e_1_2_11_3_1","first-page":"769","article-title":"Expression profile of class I histone deacetylases in human cancer tissues","volume":"18","author":"Nakagawa M","year":"2007","journal-title":"Oncol Rep"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2007.02.009"},{"key":"e_1_2_11_5_1","first-page":"6108","article-title":"MS\u201027\u2010275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors","volume":"62","author":"Jaboin J","year":"2002","journal-title":"Cancer Res"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.21988"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-007-0227-8"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.238733.114"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568009611313040005"},{"key":"e_1_2_11_10_1","unstructured":"Entinostat Investigator Brochure. Updated August2018."},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.188"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-0791"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-1461"},{"key":"e_1_2_11_14_1","unstructured":"Entinostat in Treating Pediatric Patients with Recurrent or Refractory Tumors. NCT02780804. NIH.https:\/\/clinicaltrials.gov\/ct2\/show\/. 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