Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma
| Autor: | Mitchell R. Smith, Catherine Diefenbach, Kevin R. Kelly, Andrzej Jakubowiak, Zhaowei Hua, R. Donald Harvey, Sagar Lonial, Daniel Lebovic, Bruce J. Dezube, George Mulligan, Hélène M. Faessel, Owen A. O'Connor, Jatin J. Shah, Stephen Tirrell, Robert Z. Orlowski, Allison Berger |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research medicine.medical_specialty Lymphoma Maximum Tolerated Dose NEDD8 Protein Antineoplastic Agents Cyclopentanes Pharmacology Neutropenia Gastroenterology Drug Administration Schedule Article 03 medical and health sciences Protein neddylation 0302 clinical medicine Refractory Internal medicine Medicine Humans Molecular Targeted Therapy Ubiquitins Multiple myeloma Aged Aged 80 and over business.industry Middle Aged medicine.disease 030104 developmental biology medicine.anatomical_structure Pyrimidines Treatment Outcome Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Pharmacodynamics Retreatment Female Bone marrow Drug Monitoring Neoplasm Recurrence Local business Multiple Myeloma Febrile neutropenia Biomarkers |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 22(1) |
| ISSN: | 1557-3265 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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