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• W4361951792 abstract "<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Patients with relapsed/refractory myeloma (<i>n</i> = 17) or lymphoma (<i>n</i> = 27) received intravenous pevonedistat 25 to 147 mg/m² on days 1, 2, 8, 9 (schedule A; <i>n</i> = 27) or 100 to 261 mg/m² on days 1, 4, 8, 11 (schedule B; <i>n</i> = 17) of 21-day cycles.</p><p><b>Results:</b> 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 ≥3 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–NEDD8 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(1); 34–43. ©2015 AACR</i>.</p></div>" @default.
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• W4361951792 date "2023-03-31" @default.
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• W4361951792 title "Data from Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma" @default.
• W4361951792 doi "https://doi.org/10.1158/1078-0432.c.6524544.v1" @default.
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