{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T08:58:11Z","timestamp":1794473891534,"version":"4.9.1"},"reference-count":37,"publisher":"American Association for Cancer Research (AACR)","issue":"1","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Purpose: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924\/MLN4924) in patients with relapsed\/refractory lymphoma or multiple myeloma.<\/jats:p>\n                  <jats:p>Experimental Design: Patients with relapsed\/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg\/m2 on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg\/m2 on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles.<\/jats:p>\n                  <jats:p>Results: Maximum tolerated doses were 110 mg\/m2 (schedule A) and 196 mg\/m2 (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade \u22653 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat\u2013NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease.<\/jats:p>\n                  <jats:p>Conclusions: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed\/refractory lymphoma. Clin Cancer Res; 22(1); 34\u201343. \u00a92015 AACR.<\/jats:p>","DOI":"10.1158\/1078-0432.ccr-15-1237","type":"journal-article","created":{"date-parts":[[2015,11,11]],"date-time":"2015-11-11T21:20:15Z","timestamp":1447276815000},"page":"34-43","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":184,"title":["Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed\/Refractory Multiple Myeloma or Lymphoma"],"prefix":"10.1158","volume":"22","author":[{"given":"Jatin J.","family":"Shah","sequence":"first","affiliation":[{"name":"1Lymphoma\/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej J.","family":"Jakubowiak","sequence":"additional","affiliation":[{"name":"2Section of Hematology\/Oncology, University of Chicago, Chicago, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"O'Connor","sequence":"additional","affiliation":[{"name":"3Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Z.","family":"Orlowski","sequence":"additional","affiliation":[{"name":"1Lymphoma\/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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