Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma A C

Leo I. Gordon*, Jason B. Kaplan, Rakesh Popat, Howard A. Burris, Silvia Ferrari, Sumit Madan, Manish R. Patel, Giuseppe Gritti, Dima El-Sharkawi, Ian Chau, John A. Radford, Jaime Perez de Oteyza, Pier Luigi Zinzani, Swaminathan Iyer, William Townsend, Reem Karmali, Harry Miao, Igor Proscurshim, Shining Wang, Yujun WuKate Stumpo, Yaping Shou, Cecilia Carpio, Francesc Bosch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)3546-3556
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number14
DOIs
StatePublished - Jul 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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