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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Mivavotinib | Mivavotinib | 0 | 6 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Mivavotinib | TAK-659|TAK659 | SYK Inhibitor 15 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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