Pevonedistat, a first-in-class drug that inhibits the NEDD8-activating enzyme (NAE), has been shown to be safe and to have clinical activity in patients with relapsed or refractory lymphoma or multiple myeloma.
Pevonedistat, a first-in-class drug that inhibits the NEDD8-activating enzyme (NAE), has been shown to be safe and to have clinical activity in patients with relapsed or refractory lymphoma or multiple myeloma. The results of the phase I clinical trial is published in Clinical Cancer Research.
"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," concluded Jatin J. Shah, MD, associate professor of medicine and director of myeloma clinical and translational research, and director of the lymphoma/myeloma fellowship program at The University of Texas MD Anderson Cancer Center in Houston, and colleagues.
Pevonedistat (TAK-924/MLN4924; Millennium Pharmaceuticals) is a first-in-class small molecule inhibitor of NAE, which is part of the ubiquitin-proteosome system that is administered by intravenous infusion. Proteosome inhibitors have been previously approved by the US Food and Drug Administration, including bortezomib (Velcade), which is used to treat multiple myeloma and some forms of lymphoma.
"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 Dr. Shah in a news release. "Although pevonedistat had modest activity as a single-agent treatment, 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 phase I clinical trial enrolled 44 patients--17 with relapsed/refractory multiple myeloma and 27 with relapsed/refractory lymphoma. Patients received escalating doses of pevonedistat over 1 hour on days 1, 2, 8, and 9 (schedule A) or alternatively on days 1, 4, 8, and 11 (schedule B) of 21-day cycles. The maximum tolerated doses were 110 mg/m2 for schedule A and 196 mg/m2 for schedule B.
Three lymphoma patients achieved a partial response and an additional 30 patients-17 with lymphoma and 13 with multiple myeloma-had stable disease on treatment.
Serious adverse events, including anemia, neutropenia, and pneumonia, were experienced by eight patients on each schedule. Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps for patients on dosing schedule A, and thrombocytopenia for those on schedule B.
Dr. Shah did note that since this phase I trial enrolled a small number of patients that were heavily pretreated, it may not provide a thorough assessment on how effective pevonedistat truly is.