Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma
| Autor: | Shining Wang, Cecilia Carpio, Kate Stumpo, Swaminathan P. Iyer, Jaime Pérez de Oteyza, Giuseppe Gritti, Silvia Ferrari, John Radford, Francesc Bosch, Ian Chau, William Townsend, Yaping Shou, Yujun Wu, Dima El-Sharkawi, Manish R. Patel, Igor Proscurshim, Sumit Madan, Leo I. Gordon, Pier Luigi Zinzani, Reem Karmali, Rakesh Popat, Jason B. Kaplan, Howard A. Burris, Harry Miao |
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| Přispěvatelé: | Gordon L.I., Kaplan J.B., Popat R., Burris H.A., Ferrari S., Madan S., Patel M.R., Gritti G., El-Sharkawi D., Chau I., Radford J.A., Perez de Oteyza J., Zinzani P.L., Iyer S., Townsend W., Karmali R., Miao H., Proscurshim I., Wang S., Wu Y., Stumpo K., Shou Y., Carpio C., Bosch F. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research medicine.medical_specialty TAK-659 Dual SYK/FLT3 Inhibitor B-Cell Lymphoma Follicular lymphoma Administration Oral Gastroenterology Asymptomatic Drug Administration Schedule 03 medical and health sciences Young Adult 0302 clinical medicine Refractory hemic and lymphatic diseases Internal medicine medicine Humans Syk Kinase Adverse effect B-cell lymphoma Lymphoma Follicular Protein Kinase Inhibitors Aged Aged 80 and over Dose-Response Relationship Drug Manchester Cancer Research Centre business.industry ResearchInstitutes_Networks_Beacons/mcrc Drugs Investigational Middle Aged medicine.disease Pyrrolidinones Lymphoma 030104 developmental biology Pyrimidines Treatment Outcome Oncology Tolerability fms-Like Tyrosine Kinase 3 030220 oncology & carcinogenesis Toxicity Female Lymphoma Large B-Cell Diffuse medicine.symptom business |
| Zdroj: | Gordon, L I, Kaplan, J B, Popat, R, Burris 3rd, H A, Ferrari, S, Madan, S, Patel, M R, Gritti, G, El-Sharkawi, D, Chau, I, Radford, J, Perez de Oteyza, J, Zinzani, P L, Iyer, S, Townsend, W, Karmali, R, Miao, H, Proscurshim, I, Wang, S, Wu, Y, Stumpo, K, Shou, Y, Carpio, C & Bosch, F 2020, ' Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma ', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 26, no. 14, pp. 3546-3556 . https://doi.org/10.1158/1078-0432.CCR-19-3239 |
| DOI: | 10.1158/1078-0432.CCR-19-3239 |
| Popis: | Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted. |
| Databáze: | OpenAIRE |
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