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

Li, Gordon; Kaplan, Jason; Popat, Rakesh; Burris, Howard A.; Ferrari, Silvia; Madan, Sumit; Patel, Manish R.; Gritti, Giuseppe; El‐Sharkawi, Dima; Chau, Ian; Radford, John; Oteyza, Jaime Pérez de; Zinzani, Pier Luigi; Iyer, Swaminathan P.; Townsend, William; Karmali, Reem; Miao, Harry; Proscurshim, Igor; Wang, Shining; Wu, Yujun; Stumpo, Kate; Shou, Yaping; Carpio, Cecilia; Bosch, Francesc

doi:10.1158/1078-0432.ccr-19-3239

Cited by 19 publications

(43 citation statements)

References 38 publications

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“…If SYK inhibitors in the future could also enter this pharmacological armamentarium for AML remains an unanswered question. However, our data supported an effect of SYK inhibition particularly in FLT3 mutated cases, and special TAK-659, which has inhibitory effects against both FLT3 and SYK, seems promising for use in hematological malignancies [ 18 ]. The approaches of dual SYK and FLT3 inhibition was further supported by preclinical data, indicating that SYK is a critical regulator of FLT3 in AML [ 9 ].…”

Section: Discussionsupporting

confidence: 56%

“…Several SYK inhibitors have recently been developed, and bioavailable SYK inhibitors have entered clinical trials for patients with AML [ 17 , 18 , 19 ], with promising results [ 17 , 18 , 19 , 20 , 21 ]. Previous in vitro studies in mouse models have resulted in the impaired growth of AML cells [ 2 , 10 ]; however, the underlying molecular events of SYK signaling have not been investigated in a large context [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition

Brattås

Hemsing

Rye

et al. 2022

IJMS

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. All inhibitors demonstrated a concentration-dependent antiproliferative effect, although there was considerable heterogeneity among patients. For fostamatinib and TAK-659, the antiproliferative effects were significantly higher in FLT3 mutated patients compared to nonmutated patients. Fostamatinib, entospletinib, TAK-659, and RO9021 induced significant apoptosis in primary AML cells, although the proapoptotic effects of the SYK inhibitors were less pronounced than the antiproliferative effects. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition

Brattås

Hemsing

Rye

et al. 2022

IJMS

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“…The mTORi temsirolimus was approved in 2009 in Europe for R/R MCL based on its efficacy in two phase 2 studies, showing ORR of 38%-41% in monotherapy [122,123], later confirmed in phase 3 studies, with ORR between 22%-47% [124,127]. Regarding SYKi, fostamatinib showed modest activity in monotherapy in both MCL and DLBCL in a phase 1/2 study, with ORR of 11% and 22% respectively [135] and, more recently, TAK-659, a dual inhibitor of SYK and FMS-like tyrosine kinase 3 (FLT3), showed ORR of 28% in patients with R/R DLBCL [136]. Studies evaluating these and other inhibitors of mTOR and SYK, both in monotherapy and in combination, are summarized in Table 1.…”

Section: Clinical Experience With the Targeting Of Apical Bcr Kinases In Dlbcl And MCLmentioning

confidence: 97%

Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

Profitós-Pelejà¹,

Santos²,

Marín‐Niebla³

et al. 2021

Preprint

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The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

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“…The mTORi temsirolimus was approved in 2009 in Europe for R/R MCL based on its efficacy in two phase 2 studies, showing ORR of 38-41% in monotherapy [ 121 , 122 ], later confirmed in phase 3 studies, with ORR between 22-47% [ 123 , 126 ]. Regarding SYKi, fostamatinib showed modest activity in monotherapy in both MCL and DLBCL in a phase 1/2 study, with ORR of 11% and 22%, respectively [ 148 ], and, more recently, TAK-659, a dual inhibitor of SYK and FMS-like tyrosine kinase 3 (FLT3), showed ORR of 28% in patients with R/R DLBCL [ 152 ]. Studies evaluating these and other inhibitors of mTOR and SYK, both in monotherapy and in combination, are summarized in Table 1 and Table 2 .…”

Section: Pharmacological Targeting Of Bcr Upstream Kinases and Its Li...mentioning

confidence: 99%

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

Profitós-Pelejà

Santos

Marín‐Niebla

et al. 2022

Cancers

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The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

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

Cited by 19 publications

References 38 publications

Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition

Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition

Regulation of B Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

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