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
| Autor: | Quincy Siu-Chung Chu, Sylvie Rottey, Ben Markman, Takafumi Koyama, Jean-Pascal Machiels, Paul de Souza, Kyaw L. Aung, Jeffrey M. Clarke, Heather E. Vezina, Michael Millward, Armando Santoro, Sandip Pravin Patel, Chunsheng He, Kimberley M. Heinhuis, Michelle Brown, Martijn P. Lolkema, Matteo Duca, Giuseppe Curigliano |
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| Přispěvatelé: | UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Unité d'oncologie médicale, UCL - (SLuc) Service d'oto-rhino-laryngologie, Medical Oncology |
| Rok vydání: | 2021 |
| Předmět: |
Drug
medicine.medical_specialty Cancer Research Immunoconjugates media_common.quotation_subject Gastroenterology SDG 3 - Good Health and Well-being Internal medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols Clinical endpoint Medicine and Health Sciences Medicine Humans Mesothelin Dosing IMMUNOTHERAPY Adverse effect media_common AGENT biology business.industry TUBULYSIN digestive oral and skin physiology stomatognathic diseases TARGET Nivolumab Tolerability Oncology biology.protein SURVIVAL Alkaline phosphatase OVEREXPRESSION business |
| Zdroj: | CLINICAL CANCER RESEARCH Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 28, no.1, p. 95-105 (2022) Clinical Cancer Research, 28(1), 95-105. American Association for Cancer Research Inc. |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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