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Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834208/ https://www.ncbi.nlm.nih.gov/pubmed/36631449 http://dx.doi.org/10.1038/s41408-022-00763-w |
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author | Torka, Pallawi Kambhampati, Swetha Chen, Lu Wang, Xiaoguang Chen, Canping Vuong, Dan Qin, Hanjun Muir, Alexandra Orand, Kirsten Borja, Ivana Lynne Smith, D. Herrera, Alex F. Spurgeon, Stephen E. F. Park, Byung Lewis, Lionel D. Hernandez-Ilizaliturri, Francisco Xia, Zheng Danilov, Alexey V. |
author_facet | Torka, Pallawi Kambhampati, Swetha Chen, Lu Wang, Xiaoguang Chen, Canping Vuong, Dan Qin, Hanjun Muir, Alexandra Orand, Kirsten Borja, Ivana Lynne Smith, D. Herrera, Alex F. Spurgeon, Stephen E. F. Park, Byung Lewis, Lionel D. Hernandez-Ilizaliturri, Francisco Xia, Zheng Danilov, Alexey V. |
author_sort | Torka, Pallawi |
collection | PubMed |
description | 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/m(2)); 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/m(2) 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. |
format | Online Article Text |
id | pubmed-9834208 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98342082023-01-13 Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma Torka, Pallawi Kambhampati, Swetha Chen, Lu Wang, Xiaoguang Chen, Canping Vuong, Dan Qin, Hanjun Muir, Alexandra Orand, Kirsten Borja, Ivana Lynne Smith, D. Herrera, Alex F. Spurgeon, Stephen E. F. Park, Byung Lewis, Lionel D. Hernandez-Ilizaliturri, Francisco Xia, Zheng Danilov, Alexey V. Blood Cancer J Article 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/m(2)); 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/m(2) 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. Nature Publishing Group UK 2023-01-11 /pmc/articles/PMC9834208/ /pubmed/36631449 http://dx.doi.org/10.1038/s41408-022-00763-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Torka, Pallawi Kambhampati, Swetha Chen, Lu Wang, Xiaoguang Chen, Canping Vuong, Dan Qin, Hanjun Muir, Alexandra Orand, Kirsten Borja, Ivana Lynne Smith, D. Herrera, Alex F. Spurgeon, Stephen E. F. Park, Byung Lewis, Lionel D. Hernandez-Ilizaliturri, Francisco Xia, Zheng Danilov, Alexey V. Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title | Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title_full | Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title_fullStr | Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title_full_unstemmed | Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title_short | Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma |
title_sort | pevonedistat, a nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory b-cell non-hodgkin lymphoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834208/ https://www.ncbi.nlm.nih.gov/pubmed/36631449 http://dx.doi.org/10.1038/s41408-022-00763-w |
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