mivavotinib (CB-659) / Calithera - LARVOL DELTA

Integrative machine learning and structure-based drug repurposing for identifying potent inhibitors of human SYK activity against cancer. (PubMed, Life Sci) - "Despite the investigation of inhibitors of SYK including fostamatinib, entospletinib, cerdulatinib, and TAK-659 for cancer therapy, their lack of specificity and potential off-target effects remain significant concerns...Rifabutin, darunavir, and sildenafil were found as promising SYK inhibitors, showing strong interactions and stable conformations...Our findings underscore the value of computational methods in drug discovery and advocate for further experimental validation of these compounds as SYK-targeted therapies. This study aims to advance the development of more effective and safer treatments for cancers associated with SYK overexpression."

Journal • Oncology • SYK

Combination Chemotherapy and TAK-659 as Front-Line Treatment in Treating Patients With High-Risk Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Northwestern University | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • BCL2 • BCL6 • MYC

THE SYK INHIBITRO BAY 61-3606 DIHYDROCHLORIDE INDUCES APOPTOSIS OF ACUTE MYELOID LEUKEMIA CELLS BY MODULATING PI3K/AKT?NF/κB PATHWAY (EHA 2025) - "Current SYK inhibitors like Entospletinib, Mivavotinib, and Fostamatinib face limitations due to RAS/RAF/MEK/ERK pathway activation and off-target effects. BAY 61-3606 dihydrochloride significantly inhibits the proliferation of acute myeloid leukemia (AML) cells and induces apoptosis. Mechanistically, BAY 61-3606 dihydrochloride downregulates the expression of anti-apoptotic proteins MCL-1 and BCL-XL, thereby activating the apoptotic pathway in AML cells. Additionally, it inhibits the activation of several key signaling pathways, including P-SYK, PI3K/Akt, ERK, NF/κB, and JAK/STAT."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2L1 • MCL1 • SYK

Gene Expression Profiling in Acute Myeloid Leukemia Patient Subgroups With High and Low Sensitivity Toward SYK Inhibitors. (PubMed, Hematol Oncol) - "This study investigates in vitro antiproliferative effects of SYK inhibitors on leukemia cells by analyzing 48 primary AML samples treated with five SYK inhibitors: fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021. Gene set enrichment analysis further highlighted that high-sensitivity patient samples were upregulated in pathways associated with oxidative phosphorylation and MYC targets, whereas low-sensitivity patient samples showed enrichment in TGF beta signaling and IL6 JAK STAT3 signaling. These results identify gene expression profile signatures that may predict sensitivity to SYK inhibition and underscore the potential for personalized therapeutic strategies in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IL6 • SYK • TGFB1

Combination Chemotherapy and TAK-659 as Front-Line Treatment in Treating Patients With High-Risk Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P1 | N=12 | Active, not recruiting | Sponsor: Northwestern University | Completed ➔ Active, not recruiting | Trial completion date: Dec 2024 ➔ Dec 2028

Enrollment closed • Trial completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • BCL2 • BCL6 • MYC

Combination Chemotherapy and TAK-659 as Front-Line Treatment in Treating Patients With High-Risk Diffuse Large B Cell Lymphoma (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Northwestern University | Active, not recruiting ➔ Completed | Trial completion date: Aug 2022 ➔ Dec 2024

Trial completion • Trial completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Histiocyte Rich Large B Cell Lymphoma • BCL2 • BCL6 • MYC

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors. (PubMed, ESMO Open) - "The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors."

Journal • Metastases • P1 data • P1 data • Oncology • Ovarian Cancer • Solid Tumor • SYK

Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials. (PubMed, Front Pharmacol) - " We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication."

Monotherapy • Review • Acute Myelogenous Leukemia • Dermatology • Febrile Neutropenia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • FLT3

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors. (ASCO 2024) - P1 | "The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors."

Clinical • Metastases • P1 data • Anemia • Hematological Disorders • Oncology • Ovarian Cancer • Solid Tumor • SYK

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors. (PubMed, Cancer Med) - P1b | "Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247."

Combination therapy • Journal • Metastases • P1 data • P2 data • Breast Cancer • Hematological Disorders • Oncology • Pulmonary Disease • Renal Disease • Solid Tumor • Triple Negative Breast Cancer • FLT3 • SYK

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts. (PubMed, Pediatr Blood Cancer) - "TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • FLT3 • PTPRC • SYK

The SYK inhibitor: a novel agent for improved outcomes in relapsed/refractory diffuse large B-cell lymphoma. (PubMed, Future Oncol) - No abstract available

Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • SYK

Study of Mivavotinib (CB-659) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (clinicaltrials.gov) - P2 | N=2 | Terminated | Sponsor: Calithera Biosciences, Inc | N=50 ➔ 2 | Trial completion date: Feb 2024 ➔ Feb 2023 | Recruiting ➔ Terminated; Sponsor Decision

Biomarker • Enrollment change • Trial completion date • Trial termination • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Mivavotinib, a Syk Inhibitor, in Relapsed/Refractory (R/R) Non-GCB Diffuse Large B-Cell Lymphoma (DLBCL) with or without MYD88 and/or CD79 Mutations: A Phase 2 Study (ASH 2022) - P2 | "Following standard first-line R-CHOP (or equivalent), patients must have received 2nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd-line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Result s of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts."

IO biomarker • P2 data • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • CD79B • MYD88 • SYK

TAK-659 in combination with NKTR-214 and anti-PD-1 therapy leads to complete and sustained tumor regression and immune memory in pre-clinical syngeneic models. (ASCO 2018) - P1/2,P1b; "Background: TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is being tested in combination with nivolumab in patients with advanced solid tumors (NCT02834247). NKTR-214, TAK-659 and anti-PD-1 therapy bring together complementary non-overlapping mechanisms that create a promising potential therapy, supporting the rationale for examining the clinical combination."

Combination therapy • Colorectal Cancer

[VIRTUAL] Immunological effects of SYK inhibition using TAK659 in patients diagnosed with diffuse large B cell lymphoma (AACR-II 2020) - P2 | "Overall, these findings provide initial evidence of the role of TAK 659 in potentiating the anti-tumoral immune response during treatment of DLBCL. Therefore, we believe that treatment with TAK659 can help to reinstall immune surveillance by exerting direct immunomodulatory effects which provides rationale for combination therapy not only in B-cell derived malignancies but also in solid tumors."

Clinical • IO Biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CD8 • IFNG • IL10 • LAG3 • PD-1 • SYK

TAK-659 and Paclitaxel in Treating Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=52 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | N=81 ➔ 52 | Trial completion date: Feb 2022 ➔ Feb 2023 | Trial primary completion date: Feb 2022 ➔ Feb 2023

Enrollment change • Metastases • Trial completion • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor

Phase I study of novel SYK inhibitor TAK-659 (mivavotinib) in combination with R-CHOP for front-line treatment of high-risk diffuse large B-cell lymphoma. (PubMed, EJHaem) - " A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates."

Combination therapy • Journal • P1 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • SYK

Spleen tyrosine kinase/FMS-like tyrosine kinase-3 inhibition in relapsed/refractory B-cell lymphoma, including diffuse large B-cell lymphoma: updated data with mivavotinib (TAK-659/CB-659). (PubMed, Oncotarget) - P1 | "These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934."

Journal • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Renal Disease • FLT3 • SYK

Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition. (PubMed, Int J Mol Sci) - "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. 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."

Heterogeneity • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • SYK

Phase 2 Study of the SYK Inhibitor Mivavotinib in Relapsed/Refractory (R/R) NON-GCB Diffuse Large B-cell Lymphoma (DLBCL) With or Without MYD88 and/or CD79 Mutations (PPLC 2022) - P2 | "Patients must have had ≥2 but no more than 5 prior lines of systemic anticancer therapy; following standard first-line R-CHOP (or equivalent), patients must have received 2nd line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will inform the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79bmutated DLBCL to guide further expansion in these biomarker-defined cohorts."

IO biomarker • P2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD79B • MYD88 • SYK

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma (ASH 2021) - "Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follicular lymphoma and DEL produces high CR rates; survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination."

Combination therapy • IO biomarker • P1 data • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Novel Coronavirus Disease • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • BCL2 • CD4 • MYC • SYK

A phase 1b study to evaluate TAK-659 in combination with nivolumab in patients (pts) with advanced solid tumors. (ASCO 2017) - P1,P1b/2,P1b; "Secondary endpoints include adverse events, disease control rate, duration of response, progression-free survival, overall survival, and TAK-659 pharmacokinetics. There are currently 7 pts enrolled; recruitment to the 100 mg dose-escalation cohort is ongoing."

Checkpoint inhibition • Combination therapy • P1 data • Biosimilar • Breast Cancer • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Triple Negative Breast Cancer

Population Pharmacokinetics of Mivavotinib (TAK-659), a Dual Spleen Tyrosine Kinase (SYK) and FMS-Like Tyrosine Kinase 3 (FLT3) Inhibitor, in Patients with Advanced Solid Tumors or Hematologic Malignancies. (PubMed, J Clin Pharmacol) - "Expanding eligibility by enrolling patients with moderate renal impairment in phase 1 increased the diversity of patients in early trials and allowed the model to inform dose adjustment in patients with moderate renal impairment in future trials. In addition, simulations showed median steady-state trough concentration of mivavotinib following 70 mg twice daily and 160 mg daily dosing to be commensurate with 100 ng/mL, the level leading to >90% FLT3 inhibition per ex-vivo plasma immune assays and considered a potential exposure threshold required for FLT3-driven efficacy."

Journal • PK/PD data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Renal Disease • Solid Tumor • FLT3 • SYK

A phase Ib trial of mivavotinib (TAK-659), a dual SYK/FLT3 inhibitor, in patients with relapsed/refractory acute myeloid leukemia. (PubMed, Haematologica) - "Overall, these findings indicate that the activity of mivavotinib in R/R AML is modest. Furthermore, any future clinical investigation of this agent should be undertaken with caution, particularly in thrombocytopenic patients, due to the potential bleeding risk of SYK inhibition."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • FLT3 • SYK