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First-in-class investigational therapeutic shows early promise for lymphoma patients

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To interview Jatin J. Shah, contact Julia Gunther at [email protected] or 215-446-6896.

Bottom Line: Results from a phase I clinical trial showed that the first-in-class, investigational, anticancer therapeutic pevonedistat was safe, tolerable, and had some anticancer activity in heavily pretreated patients with relapsed/refractory lymphoma.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research

Author: Jatin J. Shah, MD, associate professor of medicine, director of myeloma clinical/translational research, and director of the lymphoma/myeloma fellowship program in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston.

Background: Pevonedistat is a first-in-class, investigational small-molecule inhibitor of the NEDD8-activating enzyme, explained Shah. "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," he said.

How the Study Was Conducted: Shah and colleagues enrolled 44 patients in the phase I clinical trial, 17 with relapsed/refractory multiple myeloma and 27 with relapsed/refractory lymphoma. Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days one, two, eight, and nine of a 21-day cycle, and 17 received escalating doses of the therapeutic on schedule B, which was days one, four, eight, and 11 of a 21-day cycle.

Results: Three patients achieved a partial response: one with relapsed nodular sclerosis Hodgkin lymphoma, one with relapsed diffuse large B-cell lymphoma, and one with relapsed peripheral T-cell lymphoma. Another 30 patients, 17 with lymphoma and 13 with multiple myeloma, achieved stable disease.

The maximum tolerated doses were 110 and 196 milligrams per meter squared on schedule A and B, respectively. Serious adverse events, including anemia, neutropenia, and pneumonia, were experienced by eight patients on each schedule.

Author Comment: Shah said, "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."

Shah added that the researchers are very grateful to all the patients who enrolled in this and other trials because without patients, progress against cancer cannot be made.

Study Limitations: According to 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.

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Funding & Disclosures: The study was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Shah has a consulting or advisory role for the following companies: FORMA Therapeutics, Array BioPharma, Novartis, Celgene, Onyx, and Takeda Pharmaceutical Company Ltd.; he receives research funding from Array BioPharma, Novartis, Onyx, Celgene, and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.

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About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 35,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 101 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with almost 19,300 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.

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