TY - JOUR
T1 - Phase I study of the novel investigational NEDD8-activating enzyme inhibitor pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma
AU - Shah, Jatin J.
AU - Jakubowiak, Andrzej J.
AU - O'Connor, Owen A.
AU - Orlowski, Robert Z.
AU - Harvey, R. Donald
AU - Smith, Mitchell R.
AU - Lebovic, Daniel
AU - Diefenbach, Catherine
AU - Kelly, Kevin
AU - Hua, Zhaowei
AU - Berger, Allison J.
AU - Mulligan, George
AU - Faessel, Hélène M.
AU - Tirrell, Stephen
AU - Dezube, Bruce J.
AU - Lonial, Sagar
N1 - Funding Information:
The authors thank Dr Stephen J. Blakemore, a former employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., for helpful discussions and critical review during the development of the manuscript. The authors also thank Steve Hill of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this article, which was funded by Millennium Pharmaceuticals, Inc. This study was funded byMillenniumPharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
Copyright © 2015 AACR.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-1237
DO - 10.1158/1078-0432.CCR-15-1237
M3 - Article
C2 - 26561559
AN - SCOPUS:84954478601
SN - 1078-0432
VL - 22
SP - 34
EP - 43
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -