Findings from a Phase 1 clinical trial have revealed that pevonedistat, a first-in-class investigational anticancer therapeutic, was safe, tolerable, and displayed modest anticancer activity in pretreated patients with relapsed/refractory (r/r) lymphoma, leading researchers to believe it might be promising as a combination treatment. The study was published in the Clinical Cancer Research, a journal of the American Association for Cancer Research.
Lead researcher Jatin J. Shah, MD (director of the lymphoma/myeloma fellowship program in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston), stated in a press release, “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. 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 pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses,” he added. “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.”
Pevonedistat is a new small-molecule inhibitor of the NEDD8-activating enzyme. “This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib (Velcade), which is used to treat multiple myeloma and various types of lymphoma. Pevonedistat also alters the ability of cancer cells to repair damaged DNA,” Dr. Shah explained.
The researchers enrolled 44 patients in the clinical study, of which 17 had r/r multiple myeloma and 27 had r/r lymphoma. The first group (myeloma patients) received increasing doses of pevonedistat on schedule B, which was given on days one, four, eight and 11 of a 21-day cycle. The second group (lymphoma patients) received increasing doses of pevonedistat on schedule A, consisting of drug administration on days one, two, eight and nine of a 21-day cycle. The maximum endured doses were 110 milligrams per square meter on schedule A and 196 milligrams on schedule B.
The results revealed that three patients (one with relapsed nodular sclerosis Hodgkin lymphoma, one with relapsed diffuse large B-cell lymphoma, and one with relapsed peripheral T-cell lymphoma) had a partial response, and a total of 30 patients (17 lymphoma and 13 multiple myeloma) stabilized their disease.
Dr. Shah reported some serious adverse effects, such as anemia, neutropenia and pneumonia, were experienced by eight patients on each schedule. He also noted that this study has an important limitation in having only enrolled a small number of patients who were all strongly pretreated, which may have compromised or limited pevonedistat’s activity assessment.
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