{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:05:58Z","timestamp":1791338758347,"version":"4.3.1"},"reference-count":39,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mouse double minute\u20102 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high\u2010risk myelodysplastic syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seventy\u2010four patients (monotherapy, <jats:italic>n<\/jats:italic>\u2009=\u200957; milademetan\u2010AZA combination, <jats:italic>n<\/jats:italic>\u2009=\u200917) were treated. The maximum tolerated dose of milademetan was 160\u2009mg once daily given for the first 14\u201321\u2009days of 28\u2010day\u2009cycles as monotherapy and on Days 5\u201314 in combination with AZA. Dose\u2010limiting toxicities were gastrointestinal, fatigue, or renal\/electrolyte abnormalities. Treatment\u2010emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New <jats:italic>TP53<\/jats:italic> mutations, detected only during milademetan monotherapy, were found pre\u2010existing below standard detection frequency by droplet digital polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70028","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T08:45:19Z","timestamp":1721378719000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Phase 1 dose escalation study of the <scp>MDM2<\/scp> inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9003-0390","authenticated-orcid":false,"given":"Courtney D.","family":"DiNardo","sequence":"first","affiliation":[{"name":"Department of Leukemia The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Olin","sequence":"additional","affiliation":[{"name":"University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice S.","family":"Wang","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Care Center  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Skikne","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center  Kansas City Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics City of Hope  Duarte California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanna","family":"Kumar","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc.  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