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Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors
PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401510/ https://www.ncbi.nlm.nih.gov/pubmed/34615718 http://dx.doi.org/10.1158/1078-0432.CCR-21-1181 |
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author | Rottey, Sylvie Clarke, Jeffrey Aung, Kyaw Machiels, Jean-Pascal Markman, Ben Heinhuis, Kimberley M. Millward, Michael Lolkema, Martijn Patel, Sandip Pravin de Souza, Paul Duca, Matteo Curigliano, Giuseppe Santoro, Armando Koyama, Takafumi Brown, Michelle Vezina, Heather He, Chunsheng Chu, Quincy Siu-Chung |
author_facet | Rottey, Sylvie Clarke, Jeffrey Aung, Kyaw Machiels, Jean-Pascal Markman, Ben Heinhuis, Kimberley M. Millward, Michael Lolkema, Martijn Patel, Sandip Pravin de Souza, Paul Duca, Matteo Curigliano, Giuseppe Santoro, Armando Koyama, Takafumi Brown, Michelle Vezina, Heather He, Chunsheng Chu, Quincy Siu-Chung |
author_sort | Rottey, Sylvie |
collection | PubMed |
description | PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. RESULTS: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. CONCLUSIONS: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors. |
format | Online Article Text |
id | pubmed-9401510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-94015102023-01-05 Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors Rottey, Sylvie Clarke, Jeffrey Aung, Kyaw Machiels, Jean-Pascal Markman, Ben Heinhuis, Kimberley M. Millward, Michael Lolkema, Martijn Patel, Sandip Pravin de Souza, Paul Duca, Matteo Curigliano, Giuseppe Santoro, Armando Koyama, Takafumi Brown, Michelle Vezina, Heather He, Chunsheng Chu, Quincy Siu-Chung Clin Cancer Res Clinical Trials: Immunotherapy PURPOSE: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors. PATIENTS AND METHODS: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. RESULTS: In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. CONCLUSIONS: BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors. American Association for Cancer Research 2022-01-01 2021-10-06 /pmc/articles/PMC9401510/ /pubmed/34615718 http://dx.doi.org/10.1158/1078-0432.CCR-21-1181 Text en ©2021 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 | Clinical Trials: Immunotherapy Rottey, Sylvie Clarke, Jeffrey Aung, Kyaw Machiels, Jean-Pascal Markman, Ben Heinhuis, Kimberley M. Millward, Michael Lolkema, Martijn Patel, Sandip Pravin de Souza, Paul Duca, Matteo Curigliano, Giuseppe Santoro, Armando Koyama, Takafumi Brown, Michelle Vezina, Heather He, Chunsheng Chu, Quincy Siu-Chung Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title | Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title_full | Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title_fullStr | Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title_full_unstemmed | Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title_short | Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors |
title_sort | phase i/iia trial of bms-986148, an anti-mesothelin antibody–drug conjugate, alone or in combination with nivolumab in patients with advanced solid tumors |
topic | Clinical Trials: Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401510/ https://www.ncbi.nlm.nih.gov/pubmed/34615718 http://dx.doi.org/10.1158/1078-0432.CCR-21-1181 |
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