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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
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
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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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