A Phase 1b/2 Dose-Escalation and Cohort-Expansion Study of the Noncovalent, Reversible Bruton's Tyrosine Kinase Inhibitor, SNS-062, in Patients With B-Lymphoid Malignancies

This is an open-label Phase 1b/2 study in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)or non hodgkin's lymphoma (NHL) who have failed prior standard of care therapies including a BTK inhibitor where one is approved for the indication.

Start Date28 Apr 2017

Sponsor / Collaborator

Sunesis Pharmaceuticals, Inc.

100 Clinical Results associated with Vecabrutinib

100 Translational Medicine associated with Vecabrutinib

100 Patents (Medical) associated with Vecabrutinib

Literatures (Medical) associated with Vecabrutinib

01 Dec 2023·Molecular Case Studies

Leukemic presentation and progressive genomic alterations of MCD/C5 diffuse large B-cell lymphoma (DLBCL)

Article

Author: Nakhoda, Shazia ; Mackrides, Nicholas ; Lu, Pin ; Baldwin, Don A ; Dupoux, Vanessa ; Kim, Patricia M ; Dave, Sandeep S ; Wang, Y Lynn ; Nejati, Reza ; Pei, Jianming ; Thakkar, Devang ; Wasik, Mariusz A

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations ofCD79B,MyD88,TP53,TBL1XR1, andPIM1genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss ofTP53heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such asPRDM1loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence ofBTKandFOXO1mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.

01 Jan 2023·Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti

Waldenström's macroglobulinemia - clinical symptoms and review of therapy yesterday, today and tomorrow.

Review

Author: Boichuk, I ; Sandecká, V ; Krejčí, M ; Pour, L ; Zeman, D ; Štork, M ; Adam, Z ; Král, Z

BACKGROUNDWaldenström macroglobulinemia (WM) is a lymphoplasmocytic lymphoma with immunoglobulin M monoclonal protein. The incidence of this disease is very low (0.4/100,000), so that this disease can be regarded as an orphan's disease. It means that new drugs are often tested and registered for more frequent diseases.PURPOSEIn this review we will focus on the efficacy of the new drugs for WM.RESULTSThe current treatment options for symptomatic WM patients include alkylating agent cyclophosphamide and anti-CD20 monoclonal antibodies. Therapy with rituximab and bendamustin resulted in longer therapeutic response then therapy with rituximab, cyclophosphamide and dexamethasone. Many drugs, used in multiple myeloma (MM), shoved promising results in WM patients. Bortezomib is effective in WM, but its neurotoxicity is higher in WM than in MM patients. Therefore, new proteasome inhibitors, carfilzomib and ixazomib, are better tolerated as documented in several studies. New types of antiCD20 antibody (obinutuzumab) can be used in patients with rituximab intolerance. in five of our patients with WM, obinutuzumab and bendamustin reached deeper responses than therapies administered in previous lines of therapy. Oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone and in combination with rituximab have extended the treatment options for WM patients. New BTK inhibitors (e. g. acalabrutinib, zanubrutinib, and vecabrutinib) were tested and their lower toxicity (atrial fibrillation) was documented. Moreover, the BCL2 inhibitor venetoclax is newly tested.CONCLUSIONNew antiCD20 antibody (obinutuzumab) is of advantage in patients with WM with rituximab intolerance as well as bendamustin and new proteasome inhibitors (ixazomib and carfilzomib) or new BTK inhibitors with lower cardiotoxicity. Many of the abovementioned drugs do not have official registration for WM and can be administrated with the consent of the health care provider only. Thus, this work brings evidence of their efficacy.

10 Feb 2022·BloodQ1 · MEDICINE

Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Q1 · MEDICINE

Article

Author: Qi, Jialei ; Stilgenbauer, Stephan ; Fox, Judith A. ; Debatin, Klaus-Michael ; Taverna, Pietro ; Mertens, Daniel ; Wist, Martin ; Walliser, Claudia ; Tausch, Eugen ; Seiffert, Martina ; Dheenadayalan, Rashmi Priyadharshini ; Meyer, Lüder Hinrich ; Seyfried, Felix ; Endres, Sascha ; Jebaraj, Billy Michael Chelliah ; Roessner, Philipp M. ; Gierschik, Peter ; Müller, Annika

AbstractCovalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+ T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.

100 Deals associated with Vecabrutinib

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	US	Dana-Farber Cancer Institute, Inc.	29 Nov 2018
Diffuse Large B-Cell Lymphoma	Phase 2	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Follicular Lymphoma	Phase 1	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Marginal Zone B-Cell Lymphoma	Phase 1	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Small Lymphocytic Lymphoma	Phase 1	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Waldenstrom Macroglobulinemia	Phase 1	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Chronic Lymphocytic Leukemia	Discovery	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017
Mantle-Cell Lymphoma	Discovery	US	Sunesis Pharmaceuticals, Inc.	28 Apr 2017

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