Phase I, first-in-human trial of Bruton's tyrosine kinase inhibitor M7583 in patients with B-cell malignancies
| Autor: | Wojciech Jurczak, Simon Rule, David L. Tucker, Monika Długosz-Danecka, Pier Luigi Zinzani, Jürgen Scheele, John G. Gribben, Barbara Sarholz, Martin Dyroff, William Townsend |
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| Přispěvatelé: | Jurczak W., Rule S., Townsend W., Tucker D., Sarholz B., Scheele J., Dyroff M., Gribben J.G., Dlugosz-Danecka M., Zinzani P.L. |
| Rok vydání: | 2021 |
| Předmět: |
safety
Cancer Research medicine.medical_specialty efficacy Gastroenterology Refractory Internal medicine Neoplasms medicine Bruton's tyrosine kinase Humans In patient Adverse effect Protein Kinase Inhibitors B cell Fatigue B-Lymphocytes biology business.industry B-Lymphocyte Hematology First in human Middle Aged Diarrhea medicine.anatomical_structure Oncology BTK Vomiting biology.protein M7583 Neoplasm medicine.symptom business Human |
| Zdroj: | Leukemialymphoma. 62(10) |
| ISSN: | 1029-2403 |
| Popis: | M7583 is a potent, highly selective, covalent BTK inhibitor in development. In this phase I, first-in-human, open label, multicenter dose-escalation trial, M7583 was given at 80 mg (threedays)/160 mg (full 28-day cycle), then 300 mg/day, 600 mg/day, 900 mg/day, and 300 mg twice daily to 18 patients (median age 63years) with refractory/resistant, stage III/IV B-cell malignancies who failed prior therapy (NCT02825836). No dose-limiting toxicities were reported. Treatment-emergent adverse events (AEs) occurred in 89% of patients, treatment-related AEs in 78%, and treatment-related grade ≥3 AEs in 17%. Common AEs were diarrhea (33%), fatigue (22%), and vomiting (17%). M7583 was rapidly absorbed and exposure was dose-proportional. BTK occupancy was >95% in the 300 mg twice daily and 900 mg/day cohorts. Objective response rate was 50% and disease control rate 78%, supporting a favorable benefit:risk profile. Fasted doses up to 900 mg once daily and 300 mg twice daily were well tolerated and may be tested in future clinical studies. |
| Databáze: | OpenAIRE |
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