Investigational NAE Inhibitor Pevonedistat Shows Potential Activity in Patients With Relapsed/Refractory Lymphoma
A phase I study evaluating 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 has found preliminary evidence suggesting potential activity in heavily pretreated patients with relapsed/refractory lymphoma. The safety profile of pevonedistat in patients with multiple myeloma and lymphoma was generally tolerable. The study by Shah et al is published in Clinical Cancer Research.
Study Methodology
This phase I, dose-escalation study was conducted at eight sites in the United States between 2008 and 2012. The primary objectives were to determine the maximum tolerated dose and safety profile of pevonedistat, describe the drug's pharmacokinetic and pharmacodynamic profiles in blood, and investigate pharmacodynamic effects in skin biopsies and bone marrow aspirates (patients with bone marrow involvement only). Secondary objectives included evaluation of disease response and pharmacokinetic–pharmacodynamic relationships.
The researchers enrolled 44 patients, 17 with multiple myeloma and 27 with any B- or T-cell non-Hodgkin lymphoma, Hodgkin lymphoma, or Waldenström macroglobulinemia. All the patients had relapsed/refractory disease after two or more prior lines of therapy.
Patients received escalating doses of pevonedistat by intravenous infusion over 1 hour on days 1, 2, 8, and 9 (schedule A) or days 1, 4, 8, and 11 (schedule B) of 21-day cycles.
Study Findings
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, 17 with lymphoma and 13 with multiple myeloma, achieved stable disease.
A Feasible Therapeutic Target
“This phase I study of pevonedistat demonstrated the validity of NAE inhibition as a therapeutic target and the anticipated pharmacodynamic effects in the clinical setting. We also report the safety profile of pevonedistat in patients with multiple myeloma and lymphoma and some preliminary evidence that is suggestive of the potential for modest activity patients with relapsed/refractory lymphoma,” concluded the study authors.
“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, Associate Professor of Medicine and Director of the Lymphoma/Myeloma Fellowship Program at The University of Texas MD Anderson Cancer Center, and lead author of this study, in a statement.
“Although pevonedistat had modest activity as a single agent treatment,” he continued, “we expect greater activity when it is given in combination with standard therapy, and there are a number of combinations currently in clinical testing for acute myeloid leukemia. The pharmacodynamics data showed that pevonedistat hit its target in patients in low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk/benefit ratio of pevonedistat.”
According to Dr. Shah, a limitation of this study is that this is a phase I clinical trial that enrolled only small numbers of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.
Dr. Shah is the corresponding author of this study.
Funding for this study was provided by Millennium Pharmaceuticals, Inc. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
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