Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

被引：169

作者：

Shah, Jatin J. ^{[1
]}

Jakubowiak, Andrzej J. ^{[2
]}

O'Connor, Owen A. ^{[3
]}

Orlowski, Robert Z. ^{[1
]}

Harvey, R. Donald ^{[4
]}

Smith, Mitchell R. ^{[5
]}

Lebovic, Daniel ^{[6
]}

Diefenbach, Catherine ^{[7
]}

Kelly, Kevin ^{[8
]}

Hua, Zhaowei ^{[9
]}

Berger, Allison J. ^{[9
]}

Mulligan, George ^{[9
]}

Faessel, Helene M. ^{[9
]}

Tirrell, Stephen ^{[9
]}

Dezube, Bruce J. ^{[9
]}

Lonial, Sagar ^{[4
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Lymphoma Myeloma, Houston, TX 77030 USA

[2] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA

[3] Columbia Univ, Med Ctr, Ctr Lymphoid Malignancies, New York, NY USA

[4] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA

[5] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA

[6] Univ Michigan, Ctr Comprehens Canc, Hematol Oncol, Ann Arbor, MI 48109 USA

[7] NYU, Sch Med, Perlmutter Canc Ctr, New York, NY USA

[8] Univ So Calif, Dept Med, Los Angeles, CA USA

[9] Millennium Pharmaceut Inc, Cambridge, MA USA

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 01期

关键词：

PROTEASOME INHIBITORS; PROTEIN-DEGRADATION; RESPONSE CRITERIA; NAE INHIBITOR; UBIQUITIN; BORTEZOMIB; APOPTOSIS; LEUKEMIA; CELLS; REREPLICATION;

D O I：

10.1158/1078-0432.CCR-15-1237

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) 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/m(2) (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. (C) 2015 AACR.

引用

页码：34 / 43

页数：10

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