TAK-659, a dual SYK/FLT3 inhibitor, leads to complete and sustained tumor regression and immune memory against tumor cells upon combination with anti-PD-1 agent

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

“…3B). The longer than 12-month duration of treatment in responding patients by the data cut-off, and the CR rate of 19% (two-thirds of responders had CR; 15% ITT) reported here for DLBCL could be attributable to the role of SYK, not only in the direct targeting of tumor cells but also in local immunity, a hypothesis supported by preclinical data, which demonstrate that TAK-659 exhibits immunomodulatory effects that control tumor growth (19). These effects include inhibition of tumor-associated T-regulatory cells and MDSCs, as well as upregulation of antitumorigenic macrophages (19).…”

“…The longer than 12-month duration of treatment in responding patients by the data cut-off, and the CR rate of 19% (two-thirds of responders had CR; 15% ITT) reported here for DLBCL could be attributable to the role of SYK, not only in the direct targeting of tumor cells but also in local immunity, a hypothesis supported by preclinical data, which demonstrate that TAK-659 exhibits immunomodulatory effects that control tumor growth (19). These effects include inhibition of tumor-associated T-regulatory cells and MDSCs, as well as upregulation of antitumorigenic macrophages (19). Furthermore, responses to TAK-659 in patients with DLBCL appeared to be independent of cell-of-origin classification, as responses were observed in both GCB and non-GCB patients; however, more data are needed before making confirmatory statements about where this agent would fit in lymphoma treatment with respect to cell of origin.…”

“…The estimated sample sizes for the DLBCL and iNHL expansion cohorts were based on a Simon 2-stage design using the following parameters: a 1-sided test at the significance level of =0.1, a power of 80%, a null hypothesis of an ORR of ≤20% for DLBCL and ≤35% for iNHL, and an alternative hypothesis of an ORR of ≥40% for DLBCL and ≥60% for iNHL. A total of 12-25 DLBCL patients (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) patients projected based on a 15% dropout rate) and 10-23 iNHL patients (14-27 patients projected based on a 15% dropout rate) would be needed for the expansion cohorts.…”

“…TAK-659 has demonstrated inhibitory activity in preclinical models of diffuse large B-cell lymphoma (DLBCL), in a RL follicular lymphoma (FL) cell line (17), and in chronic lymphocytic leukemia (CLL) cells (18). Preclinical studies in multiple syngeneic or xenograft models have also shown that TAK-659 administration can result in reductions in immunosuppressive cell populations, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells, which are mediated by both SYK and FLT3 signaling (19), suggesting an immune-modulating effect (20, 21 Based on these preclinical data, we conducted a first-in-human study of TAK-659 to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of TAK-659 in patients with solid tumors and B-cell lymphomas. Four dose levels of TAK-659 were explored in patients with relapsed/refractory solid tumors or lymphomas (60, 80, 100, and 120 mg).…”

Population Pharmacokinetics of Mivavotinib (TAK‐659), a Dual Spleen Tyrosine Kinase and FMS‐Like Tyrosine Kinase 3 Inhibitor, in Patients With Advanced Solid Tumors or Hematologic Malignancies

“…The clinical development of mivavotinib was pursued following the demonstration of preclinical antineoplastic and immunomodulatory activity in cell lines and animal models of human B-cell malignancies, solid tumors, and AML. [8][9][10] The safety, preliminary efficacy, and pharmacokinetics (PK) of single-agent mivavotinib have been investigated in 2 open-label, multicenter, clinical studies: (1) a phase 1, first-in-human, dose-escalation and expansion study in adult patients with advanced solid tumors or relapsed/refractory B-cell lymphomas (C34001; clinicaltrials.gov identifier, NCT02000934) 11 ; and (2) a phase 1b/2, dose-escalation and expansion study in adult patients with relapsed/refractory AML (C34002; clinicaltrials.gov identifier, NCT02323113). 12 In study C34001, continuous, once-daily (QD) mivavotinib (60-120 mg) was generally well tolerated and demonstrated encouraging activity in patients with B-cell lymphoma (overall response rate [ORR], 28% [19% complete response, CR] in diffuse large B-cell lymphoma and 89% [22% CR] in follicular lymphoma), supporting further exploration in these patients, both as monotherapy and in combinations.…”