Velexbru (tirabrutinib)

P1, N=203, Active, not recruiting, Gilead Sciences | Phase classification: P1b --> P1

For example, BTK C481S mutation is well known as a resistant mutation to covalent BTK inhibitors and several mutations of BTK (such as T474I and L528W mutation) have recently been reported in relapsed or refractory CLL patients with acquired resistance to pirtobrutinib, a non-covalent BTK inhibitor...ONO-7018 and tirabrutinib were orally administered to the mice twice a day... ONO-7018 would provide novel therapeutic strategies to overcome the BTK inhibitor acquired resistance and enhance the antitumor effect of BTK inhibitors in clinic. Phase 1 study of ONO-7018 (NCT05515406) is currently ongoing.

TIR responses were observed in all patient subpopulations, and the baseline KPS was suggested to be associated with long-term response. KPS and QoL were generally maintained during the long-term observation period.

We here present real-world data from the German CLL Study Group (GCLLSG) registry and report outcomes and treatment sequences of pts treated with either BCL2i (venetoclax) or BTKi (acalabrutinib, ibrutinib, spebrutinib, tirabrutinib, or zanubrutinib) as first administered targeted agent. EFS, TTNT and OS were comparable following Ven versus BTKi-based therapy in pts documented in the GCLLSG registry between 2014 and 2023.

Because he had severe neuropathy, he received rituximab as symptomatic WM...He already received alphacalcidol 0.5 μg/day and alendronate 35 mg weekly...Sodium phosphate monobasic and tirabrutinib was initiated. Three months after treatment, serum IgM decreased to 423 mg/dl, and serum phosphate increased to 3.7 mg/dl. From the previous report, there are only three types of hematological malignancy that cause FGF23-related hypophosphatemia: diffuse large B-cell lymphoma, natural killer T-cell lymphoma and acute leukemia. We should also consider WM induce FGF23-related hypophosphatemia.

Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development.

Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm...One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.

No abstract available

In the phase III iNNOVATE study, the combination of rituximab and ibrutinib was compared with rituximab and placebo in treatment-naïve and relapsed/refractory patients. Second-generation BTK inhibitor, zanubrutinib, was compared with Ibrutinib in MYD88-mutated WM patients in the phase III ASPEN trial, whereas acalabrutinib was investigated in a phase II trial. Here, we discuss the role of BTK inhibitors in treatment-naïve patients with WM based on currently available evidence.

Methotrexate intravitreal injections are effective in controlling ocular lesions; however, this treatment allows CNS dissemination...Ibrutinib, lenalidomide with or without rituximab, and temozolomide are promising treatments for relapsed/refractory VRL. In Japan, Bruton's tyrosine kinase (BTK) inhibitors have been approved for treating refractory CNS lymphoma. Furthermore, a randomized prospective study of tirabrutinib, a highly selective BTK inhibitor, is ongoing for evaluating the suppressing of CNS progression in patients with PVRL.

Small molecule Bruton's tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013...Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway...Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.

In vitro kinase assays showed that, compared with ibrutinib, tirabrutinib and other second-generation BTK inhibitors demonstrated a highly selective kinase profile. Transcriptomic analysis indicated that IRF4 gene expression signatures had decreased in the tirabrutinib groups. In conclusion, tirabrutinib exerted an anti-tumor effect by regulating multiple BTK downstream signaling proteins, such as NF-κB, AKT, and ERK, in ABC-DLBCL.

Introduction: Bruton's tyrosine Kinase (Btk) plays an essential role in BCR signaling and has been a hot new target in molecular targeted therapy in the past few years, led by the clinical success of ibrutinib and acalabrutinib, two first approved BTK inhibitors, that greatly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Currently, there are 5 approved BTK inhibitors including additionally zanubrutinib, orelabrutinib and velexbru... The Ba/F3-BTK engineering cell lines can be a useful tool to develop and evaluate next-generation BTK inhibitors and to explore new acquired resistance BTK mutations.

However, the patient continued treatment after abdominal computed tomography showed that splenomegaly and lymphadenopathy had improved, and the patient recovered from leukocytosis. There are no reports that leukocytosis is a side effect of tirabrutinib; therefore, this case can be considered unique.

Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients...In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standardof-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustinebased therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients...In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib...Acalabrutinib, originally referred to as ACP-196, is a novel, irreversible BTK inhibitor that was designed to be more kinase-selective than ibrutinib. Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed the treatment of B cell malignancies and autoimmune diseases. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. Zilovertamab vedotin is an antibodydrug conjugate, which binds specifically to receptor tyrosine kinase-like orphan receptor-1 (ROR-1), an oncoprotein that is pathologically expressed in mantle cell lymphoma and other malignancies. The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.

Standard care for newly diagnosed patients with PCNSL comprised induction with high-dose methotrexate (HD-MTX)-based multi-agent immunochemotherapy, such as R-MPV (rituximab, MTX, procarbazine, vincristine) yielding 70-75% complete response rate, followed by HD-cytarabine consolidation. Consolidation high-dose chemotherapy with the key drug thiotepa supported by autologous stem cell transplant has recently been investigated to replace WBRT in multiple randomized trials, demonstrating non-inferiority to WBRT with less neurotoxicity...Furthermore, tirabrutinib, a second-generation BTK inhibitor, has shown substantial activity against relapsed/refractory PCNSL, resulting in its approval in 2020 in Japan. Additionally, other new agents against PI3-kinase and immunotherapies including immunomodulatory agents, immune checkpoint blockade, and CAR-T have been actively tested in clinical trials.

It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.

In July 2020, BR (bendamustine, rituximab) therapy was administered, but it was ineffective. This is the second report of successful treatment of BNS with tirabrutinib. More research is needed to confirm tirabrutinib's efficacy in the treatment of BNS.

Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.

The first-generation BTK inhibitor ibrutinib has been widely studied in clinical trials for PCNSL and systemic non-GCB DLBCL. In Japan, a second-generation BTK inhibitor tirabrutinib was studied in a phase I/II trial and approved by the Japanese Ministry of Health and Welfare in March 2020 for relapsed and refractory PCNSL. While the current standard-of-care therapy for PCNSL is methotrexate(MTX)-based multi-agent induction immunochemotherapy like R-MPV(rituximab, MTX, procarbazine, and vincristine)followed by consolidation chemotherapy and/or radiation therapy, further investigation into the optimal use of BTK inhibitors in the standard-of-care therapy of PCNSL is warranted.

The INNOVATE study randomized 150 patients with WM to either the combination of ibrutinib plus rituximab or placebo plus rituximab.2 The combination of ibrutinib plus rituximab was associated with a higher major response rate (72% versus 32%) and a higher 30-month PFS rate (82% versus 28%) than the combination of placebo plus rituximab, prompting the approval of the combination of ibrutinib plus rituximab for WM by the FDA in 2018...Three novel covalent BTK inhibitors are under active investigation for WM: zanubrutinib, acalabrutinib and tirabrutinib...The non-covalent BTK inhibitor pirtobrutinib was evaluated in a multicenter phase Iistudy in 26 patients with WM of whom 18 (12 had progressed and 6 were intolerant) were previously exposed to a covalent BTK inhibitor.6 The ORR to pirtobrutinib was 69%...A study evaluating the combination of ibrutinib and venetoclax in treatment-naïve patients with WM is ongoing...The CXCR4 inhibitor mavorixafor is being evaluated in combination with ibrutinib in WM patients who carry CXCR4 mutations. The PI3K inhibitor idelalisib show early efficacy in patients with WM but it seems to be associated with a high rate of liver toxicity.8 A multicenter study evaluating umbralisib in patients with WM has stopped accrual. The anti-CD38 monoclonal antibody daratumumab had a lower-than-expected efficacy rate in WM.9 Dasatanib is an HCK inhibitor being studied in patients with WM progressing on covalent BTK inhibitors. The phospholipid-drug conjugate CLR-131 was recently granted a Fast- Track Designation for WM patients having received two or more prior treatment regimens. In all, the treatment of patients with WM continues evolving. There are many reasons to be optimistic about the future of the treatment landscape of patients with WM.

Ibrutinib inhibits migration of CLL cells towards chemokines such as CXCL12 and 13 and prevents secretion of BCR-dependent chemokines CCL3 and CCL4, suggesting that treatment inhibits homing and retention of malignant cells in their survival niches (de Gorter et al 2007, Ponader 2012), thus suggesting resistance may be mediated via alterations of cell migration and localisation (although the roles in DLBCL cell line models remain unclear). Overall, these data show that resistance to tirabrutinib is mediated by rapid and profound changes in gene expression as well as non- transcriptional mechanisms affecting BCR and chemokine receptor signalling as well as metabolic changes.

Ibrutinib was the most used BTKi (71%), followed by acalabrutinib (17%), zanubrutinib (9·5%) and tirabrutinib (2·5%)...All patients with mutated BTK were alive; next therapy with good response was started in two cases, although one relapsed after 14 months of venetoclax...However, only a proportion of patients developed these anomalies, suggesting that other unknown mechanisms may contribute to drug resistance. For this reason, different therapeutic strategies, with new drugs and combinations, and possible intermittent treatment with BTKi should be studied to avoid or bypass BTK and PLCG2 mutations.

Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.

According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.

The differentially expressed gene (DEGs) of four expression profiles datasets (GSE5438, GSE40595, GSE38666 and GSE26712) were collected from Gene Expression Omnibus (GEO) database and analyzed with NetworkAnalyst...The mRNA-miRNA-lncRNA networks (TACC3-hsa-miR-425-5p-FUT8-AS1 and CXCR4-hsa-miR-146a-5p-LINC00665/LINC01535) were eventually constructed in OC based on ceRNA mechanism. We successfully constructed novel ceRNA network associated with the prognosis of ovarian cancer, which may provide a new strategy for early diagnosis and therapeutic intervention of OC.

In summary, the data may produce new insights regarding OC pathogenesis and treatment. Hub genes and candidate drugs may improve individualized diagnosis and therapy for OC in future.

Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).

Molecular targeted therapies have changed the landscape of treatment strategies for B-NHLs since the approval of rituximab, an anti-CD20 monoclonal antibody, by the US Food and Drug Administration in 1997...However, there are unique toxicities that need to be resolved. It is necessary to find out the toxicity mechanism; optimal treatment strategy for these toxicities; and novel targeted therapies which might potentially overcome the toxicities of previously approved targeted therapies.

These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.

TIRA in combination with IDELA or ENTO was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over TIRA alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).

LINC01210 is upregulated in OC and predicts a poor prognosis. It accelerates proliferation, invasion and migration in OC cells through epigenetically downregulating KLF4.

The expression profiles GSE27651, GSE38666, GSE40595, and GSE66957 including 188 tumor and 52 nontumor samples were downloaded from the Gene Expression Omnibus database...We next identified four bioactive compounds (vorinostat, LY-294002,trichostatin A, and tanespimycin) based on ConnectivityMap...Furthermore, the univariate and multivariate Cox proportional hazards regression showed that ZWINT was independent prognostic indictor among EOC patients. The genes and pathways discovered in the above studies may open a new direction for EOC treatment.

A triple combination with tirabrutinib, entospletinib, and obinutuzumab (TEO regimen) was tolerable and demonstrated excellent therapeutic activity in pts with relapsed or refractory CLL, but with limited CR rate.

Combination therapy with tirabrutinib, idelalisib, and obinutuzumab (TIO regimen) had good efficacy with some relevant toxicity in relapsed/refractory CLL.