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Supplementary Tables 1-6, Supplementary Figure Legend from Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

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posted on 2023-03-31, 19:05 authored by Jatin J. Shah, Andrzej J. Jakubowiak, Owen A. O'Connor, Robert Z. Orlowski, R. Donald Harvey, Mitchell R. Smith, Daniel Lebovic, Catherine Diefenbach, Kevin Kelly, Zhaowei Hua, Allison J. Berger, George Mulligan, Hélène M. Faessel, Stephen Tirrell, Bruce J. Dezube, Sagar Lonial

Table A1. Prior therapies received (agents received by >5 patients); Table A2. Summary of pevonedistat plasma pharmacokinetic parameters on days 1 and 9 of cycle 1 on schedule A (administration on days 1, 2, 8, 9 of 21-day cycles); Table A3. Summary of pevonedistat plasma pharmacokinetic parameters on days 1 and 4 (or, alternatively, day 11) of cycle 1 on schedule B (administration on days 1, 4, 8, 11 of 21-day cycles); Table A4. Changes from baseline in gene expression levels for NAEregulated transcriptional targets on cycle 1, day 1 following pevonedistat administration at the MTDs on schedules A and B; Table A5. Patients achieving partial responses; Table A6. Patients achieving stable disease and receiving at least 5 cycles of pevonedistat.

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ARTICLE ABSTRACT

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.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.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 ≥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.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); 34–43. ©2015 AACR.