Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
In: Blood Cancer Journal, Jg. 13 (2023), Heft 1, S. 1-9
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Zugriff:
Abstract Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.
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Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
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Autor/in / Beteiligte Person: | Torka, Pallawi ; Kambhampati, Swetha ; Chen, Lu ; Wang, Xiaoguang ; Chen, Canping ; Vuong, Dan ; Qin, Hanjun ; Muir, Alexandra ; Orand, Kirsten ; Borja, Ivana ; D. Lynne Smith ; Herrera, Alex F. ; Spurgeon, Stephen E. F. ; Park, Byung ; Lewis, Lionel D. ; Hernandez-Ilizaliturri, Francisco ; Xia, Zheng ; Danilov, Alexey V. |
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Zeitschrift: | Blood Cancer Journal, Jg. 13 (2023), Heft 1, S. 1-9 |
Veröffentlichung: | Nature Publishing Group, 2023 |
Medientyp: | academicJournal |
ISSN: | 2044-5385 (print) |
DOI: | 10.1038/s41408-022-00763-w |
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