{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T23:32:08Z","timestamp":1784935928311,"version":"3.55.0"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,2]],"date-time":"2021-02-02T00:00:00Z","timestamp":1612224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>The investigational NEDD8\u2010activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single\u2010agent azacitidine in patients with higher\u2010risk myelodysplastic syndrome (higher\u2010risk MDS), higher\u2010risk chronic myelomonocytic leukemia (higher\u2010risk CMML), or low\u2010blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia\u2010inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug\u2010related and disease\u2010related intrinsic and extrinsic factors. A PubMed literature review (January 2000\u2013November 2019) supported similarity in epidemiology of higher\u2010risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS\/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose\u2010escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug\u2010related and disease\u2010related intrinsic and extrinsic factors supported design of an Asia\u2010inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~\u00a030 East Asian patients (of ~\u00a0450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia\u2010inclusive MRCTs.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"box\" position=\"anchor\"><jats:caption><jats:title>Study Highlights<\/jats:title><\/jats:caption><jats:p>\n<jats:list list-type=\"simple\">\n\n<jats:list-item><jats:p>\n<jats:bold>WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?<\/jats:bold>\n<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p>Azacitidine is the standard of care for myelodysplastic syndromes\/low\u2010blast acute myeloid leukemia (AML) across Western and East Asian patients. The first\u2010in\u2010class small\u2010molecule inhibitor of NEDD8\u2010activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>WHAT QUESTION DID THIS STUDY ADDRESS?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian\u2010inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug\u2010related and disease\u2010related intrinsic and extrinsic factors.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>These analyses provide scientific rationale for Asia\u2010inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy.\n<jats:list list-type=\"simple\">\n<jats:list-item><jats:p><jats:bold>HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?<\/jats:bold><\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><jats:p>We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia\u2010inclusive multiregional clinical trials.<\/jats:p><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/cts.12972","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T19:19:55Z","timestamp":1611775195000},"page":"1069-1081","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Asia\u2010inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial"],"prefix":"10.1111","volume":"14","author":[{"given":"Xiaofei","family":"Zhou","sequence":"first","affiliation":[{"name":"Millennium Pharmaceuticals, Inc. 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