{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:31:41Z","timestamp":1785735101476,"version":"3.56.0"},"reference-count":29,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["UM1CA228823"],"award-info":[{"award-number":["UM1CA228823"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM 08685"],"award-info":[{"award-number":["T32GM 08685"]}],"id":[{"id":"10.13039\/100000057","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":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Outcomes for children with relapsed\/refractory (R\/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD\u20108 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20\u00a0mg\/m<jats:sup>2<\/jats:sup> days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza\u2010FLA) in children with R\/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13\u00a0years (range 1\u201321). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, 83%), acute monocytic leukemia (<jats:italic>n<\/jats:italic>\u00a0=\u00a01), and therapy\u2010related AML (<jats:italic>n<\/jats:italic>\u00a0=\u00a01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean\u00a0\u00b1\u00a0SD (<jats:italic>n<\/jats:italic>\u00a0=\u00a012) <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>, <jats:italic>V<\/jats:italic><jats:sub>SS<\/jats:sub>, <jats:italic>T<\/jats:italic><jats:sub>1\/2<\/jats:sub>, and CL were 223\u00a0\u00b1\u00a091\u00a0ng\/mL, 104\u00a0\u00b1\u00a053.8\u00a0L\/m<jats:sup>2<\/jats:sup>, 4.3\u00a0\u00b1\u00a01.2\u00a0hours, and 23.2\u00a0\u00b1\u00a06.9\u00a0L\/h\/m<jats:sup>2<\/jats:sup>, respectively. <jats:italic>T<\/jats:italic><jats:sub>1\/2<\/jats:sub>, <jats:italic>V<\/jats:italic><jats:sub>SS<\/jats:sub>, and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>, but not CL, were significantly different between age groups. The overall response rate was 25%, with <jats:italic>n<\/jats:italic>\u00a0=\u00a03 patients achieving a complete remission with incomplete hematologic recovery (CRi).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Pevonedistat 20\u00a0mg\/m<jats:sup>2<\/jats:sup> combined with Aza\u2010FLA was tolerable in children with R\/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza\u2010FLA combination demonstrated significant anti\u2010leukemic activity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.30672","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T03:15:24Z","timestamp":1694747724000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed\/refractory AML: Results from COG ADVL1712"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9717-2973","authenticated-orcid":false,"given":"Katherine","family":"Tarlock","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Hematology\/Oncology Seattle Children's Hospital, University of Washington  Seattle Washington USA"},{"name":"Clinical Research Division Fred Hutchinson Cancer Research Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Liu","sequence":"additional","affiliation":[{"name":"Children's Oncology Group  Monrovia California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles G.","family":"Minard","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Translational Research Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emasenyie A.","family":"Isikwei","sequence":"additional","affiliation":[{"name":"Department of Oncology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel M.","family":"Reid","sequence":"additional","affiliation":[{"name":"Department of Oncology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terzah M.","family":"Horton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Texas Children's Hospital, Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Fox","sequence":"additional","affiliation":[{"name":"Cancer Center St Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda J.","family":"Weigel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Pediatric Hematology and Oncology University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1203-2371","authenticated-orcid":false,"given":"Todd","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Hematology\/Oncology Seattle Children's Hospital, University of Washington  Seattle Washington 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