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Ref Type Journal Article
PMID (32327472)
Authors Gordon LI, Kaplan JB, Popat R, Burris HA, Ferrari S, Madan S, Patel MR, Gritti G, El-Sharkawi D, Chau I, Radford JA, Pérez de Oteyza J, Zinzani PL, Iyer S, Townsend W, Karmali R, Miao H, Proscurshim I, Wang S, Wu Y, Stumpo K, Shou Y, Carpio C, Bosch F
Title Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2020 Apr 23
URL
Abstract Text 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 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.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).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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Mivavotinib TAK-659|TAK659 SYK Inhibitor 14 Mivavotinib (TAK-659) is an inhibitor of spleen tyrosine kinase (SYK), which may lead to B-cell inhibition and antitumor activity (PMID: 32327472).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown mantle cell lymphoma not applicable Mivavotinib Case Reports/Case Series Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 33% (1/3, 1 partial responses) in patients with relapsed or refractory mantle cell lymphoma, with a median duration of response of 109 days (PMID: 32327472; NCT02000934). 32327472
Unknown unknown diffuse large B-cell lymphoma not applicable Mivavotinib Phase I Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 28% (12/43, 8 complete responses, 4 partial responses) in patients with relapsed or refractory diffuse large B-cell lymphoma, with a median duration of response not reached (PMID: 32327472; NCT02000934). 32327472
Unknown unknown non-Hodgkin lymphoma not applicable Mivavotinib Case Reports/Case Series Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 73% (11/15, 4 complete responses, 7 partial responses) in patients with relapsed or refractory indolent non-Hodgkin lymphoma, with a median duration of response of 176 days (PMID: 32327472; NCT02000934). 32327472
Unknown unknown lymphoma not applicable Mivavotinib Phase I Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 40% (27/67, 12 complete responses, 15 partial responses) in patients with relapsed or refractory diffuse large B-cell lymphoma, with a median duration of response of 856 days (PMID: 32327472; NCT02000934). 32327472
Unknown unknown follicular lymphoma not applicable Mivavotinib Case Reports/Case Series Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 89% (8/9, 2 complete responses, 6 partial responses) in patients with relapsed or refractory follicular lymphoma, with a median duration of response of 137 days (PMID: 32327472; NCT02000934). 32327472
Unknown unknown chronic lymphocytic leukemia not applicable Mivavotinib Case Reports/Case Series Actionable In a Phase I trial, Mivavotinib (TAK-659) treatment resulted in an objective response rate of 60% (3/5, 3 partial responses) in patients with relapsed or refractory chronic lymphocytic leukemia, with a median duration of response not reached (PMID: 32327472; NCT02000934). 32327472