TY - JOUR
T1 - Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma A C
AU - Gordon, Leo I.
AU - Kaplan, Jason B.
AU - Popat, Rakesh
AU - Burris, Howard A.
AU - Ferrari, Silvia
AU - Madan, Sumit
AU - Patel, Manish R.
AU - Gritti, Giuseppe
AU - El-Sharkawi, Dima
AU - Chau, Ian
AU - Radford, John A.
AU - de Oteyza, Jaime Perez
AU - Zinzani, Pier Luigi
AU - Iyer, Swaminathan
AU - Townsend, William
AU - Karmali, Reem
AU - Miao, Harry
AU - Proscurshim, Igor
AU - Wang, Shining
AU - Wu, Yujun
AU - Stumpo, Kate
AU - Shou, Yaping
AU - Carpio, Cecilia
AU - Bosch, Francesc
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/7/15
Y1 - 2020/7/15
N2 - 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 ¼ 36 (solid tumors, n ¼ 19; lymphoma, n ¼ 17); expansion, n ¼ 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.
AB - 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 ¼ 36 (solid tumors, n ¼ 19; lymphoma, n ¼ 17); expansion, n ¼ 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.
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U2 - 10.1158/1078-0432.CCR-19-3239
DO - 10.1158/1078-0432.CCR-19-3239
M3 - Article
C2 - 32327472
AN - SCOPUS:85088243150
SN - 1078-0432
VL - 26
SP - 3546
EP - 3556
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -