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The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Brigimadlin (BI 907828) is an oral MDM2–p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for Cancer Research
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10401071/ https://www.ncbi.nlm.nih.gov/pubmed/37269344 http://dx.doi.org/10.1158/2159-8290.CD-23-0153 |
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author | LoRusso, Patricia Yamamoto, Noboru Patel, Manish R. Laurie, Scott A. Bauer, Todd M. Geng, Junxian Davenport, Teffany Teufel, Michael Li, Jian Lahmar, Mehdi Gounder, Mrinal M. |
author_facet | LoRusso, Patricia Yamamoto, Noboru Patel, Manish R. Laurie, Scott A. Bauer, Todd M. Geng, Junxian Davenport, Teffany Teufel, Michael Li, Jian Lahmar, Mehdi Gounder, Mrinal M. |
author_sort | LoRusso, Patricia |
collection | PubMed |
description | Brigimadlin (BI 907828) is an oral MDM2–p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). SIGNIFICANCE: We report phase Ia data indicating that the oral MDM2–p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749 |
format | Online Article Text |
id | pubmed-10401071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-104010712023-08-05 The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study LoRusso, Patricia Yamamoto, Noboru Patel, Manish R. Laurie, Scott A. Bauer, Todd M. Geng, Junxian Davenport, Teffany Teufel, Michael Li, Jian Lahmar, Mehdi Gounder, Mrinal M. Cancer Discov Research Articles Brigimadlin (BI 907828) is an oral MDM2–p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). SIGNIFICANCE: We report phase Ia data indicating that the oral MDM2–p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749 American Association for Cancer Research 2023-08-04 2023-06-03 /pmc/articles/PMC10401071/ /pubmed/37269344 http://dx.doi.org/10.1158/2159-8290.CD-23-0153 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles LoRusso, Patricia Yamamoto, Noboru Patel, Manish R. Laurie, Scott A. Bauer, Todd M. Geng, Junxian Davenport, Teffany Teufel, Michael Li, Jian Lahmar, Mehdi Gounder, Mrinal M. The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title | The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title_full | The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title_fullStr | The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title_full_unstemmed | The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title_short | The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study |
title_sort | mdm2–p53 antagonist brigimadlin (bi 907828) in patients with advanced or metastatic solid tumors: results of a phase ia, first-in-human, dose-escalation study |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10401071/ https://www.ncbi.nlm.nih.gov/pubmed/37269344 http://dx.doi.org/10.1158/2159-8290.CD-23-0153 |
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