Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3546-3556 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 26 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2020 |
Funding
R. Popat is an employee/paid consultant for, reports receiving speakers’ bureau honoraria from, and reports receiving other remuneration from Takeda. S. Madan reports receiving speakers’ bureau honoraria from and is an advisory board member/ unpaid consultant for Takeda. G. Gritti reports receiving speakers’ bureau honoraria from IQVIA. D. El-Sharkawi reports receiving speakers’ bureau honoraria from Abbvie and Janssen, and is an advisory board member/unpaid consultant for Abbvie. I. Chau is an employee/paid consultant for Bristol-Myers Squibb, Eli-Lilly, MSD, AstraZeneca, Roche, Merck-Serono, Oncologie International, Pierre Fabre, and Bayer; and reports receiving commercial research grants from Eli-Lilly and Janssen Cilag. J.A. Radford reports receiving commercial research grants from Takeda and reports receiving speakers bureau honoraria from speaker engagements. J.P. de Oteyza is an employee/paid consultant for and reports receiving commercial research grants from Takeda. S. Iyer reports receiving commercial research grants from Takeda, Rhizen, Seattle Genetics, and Merck. R. Karmali reports receiving other commercial research support from Takeda, BMS, Kite/Gilead, BMS/Celgene/Juno; reports receiving speakers bureau honoraria from Kite/Gilead, AstraZeneca, BeiGene; and is an advisory board member/unpaid consultant for BMS/Celgene/Juno, Kite/Gilead, and Karyopharm. H. Miao, I. Proscurshim, and S. Wang are employees/paid consultants for Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a The authors thank the study participants and their families, and the staff at all study centers. Research was sponsored by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The authors also acknowledge Emily Sheldon-Waniga (Millennium Pharmaceuticals, Inc.) for statistical analyses, Helen Wilkinson, PhD (FireKite, an Ashfield Company, part of UDG Healthcare plc), for medical writing support, which was funded by Millennium Pharmaceuticals, Inc., and Janice Y. Ahn, PhD, and Marcel Kuttab PharmD (Millennium Pharmaceuticals, Inc.) for editorial support in compliance with Good Publication Practice 3 ethical guidelines (Battisti et al, Ann Intern Med 2015;163:461–4). Dr. Popat is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
ASJC Scopus subject areas
- General Medicine
