A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies
| Autor: | Tomoya Ohno, Claire V. Hutchinson, John Sharpe, Guillaume Cartron, Gilles Salles, Simon Rule, Franck Morschhauser, Hideyuki Honda, Bruno Cazin, Virginia Jamieson, Shin-ichiro Abe, Lionel Karlin, Toshio Yoshizawa, Harriet S. Walter, Akihisa Nishimura, Philippe Quittet, Martin J. S. Dyer, Kevin J. Duffy, Nimish Shah, Joseph Birkett, Ceri Jones, Christopher Fegan, Nigel Courtenay-Luck |
|---|---|
| Přispěvatelé: | Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Lymphocytosis Lymphoma Clinical Trials and Observations Chronic lymphocytic leukemia Phases of clinical research Lymphoma Mantle-Cell Biochemistry Gastroenterology Cohort Studies 0302 clinical medicine hemic and lymphatic diseases London Agammaglobulinaemia Tyrosine Kinase 80 and over Medicine Chronic ComputingMilieux_MISCELLANEOUS Aged 80 and over B-Lymphocytes Hematoma Leukemia Imidazoles Hematology Middle Aged Protein-Tyrosine Kinases Diffuse Lymphocytic 3. Good health drug therapy Local 030220 oncology & carcinogenesis Female Lymphoma Large B-Cell Diffuse France medicine.symptom Adult Diarrhea medicine.medical_specialty Patients Immunology [SDV.CAN]Life Sciences [q-bio]/Cancer 03 medical and health sciences Refractory blood Internal medicine Large B-Cell Humans Adverse effect Protein Kinase Inhibitors Aged therapy business.industry B-Cell toxicity Cell Biology Mantle-Cell medicine.disease Leukemia Lymphocytic Chronic B-Cell Surgery 030104 developmental biology Neoplasm Recurrence Pyrimidines antagonists & inhibitors therapeutic use drug effects adverse effects Mantle cell lymphoma pathology Neoplasm Recurrence Local business Progressive disease |
| Zdroj: | Blood Blood, American Society of Hematology, 2016, 127 (4), pp.411-419. ⟨10.1182/blood-2015-08-664086⟩ |
| ISSN: | 0006-4971 1528-0020 |
| Popis: | We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|