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  • ||||||||||  Journal:  New treatments for systemic mastocytosis in 2025. (Pubmed Central) -  Jun 5, 2025   
    Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results.
  • ||||||||||  elenestinib (BLU-263) / Blueprint Medicines, bezuclastinib (PLX9486) / Cogent Biosci, Ayvakit (avapritinib) / Blueprint Medicines
    FMC60: Mastocytosis and mast cell activation syndromes: diagnostic and therapeutic progress in 2024. (Room 352A) -  Nov 29, 2024 - Abstract #JDP2024JDP_506;    
    Other TKIs, such as elenestinib and bezuclastinib, are in phase 2 trials...Educational objectives The educational objectives are to better understand mast cell pathologies and what to do when faced with a patient with a suspicion or diagnosis of mast cell pathology with a therapeutic proposal. Content of this training Clinical cases, new developments, literature review and sharing of experience.
  • ||||||||||  bezuclastinib (PLX9486) / Cogent Biosci
    Apex Part 2 Trial in Progress: A Phase 2 Open-Label Clinical Study of Bezuclastinib in Adult Patients with Advanced Systemic Mastocytosis (Halls G-H (San Diego Convention Center)) -  Nov 21, 2024 - Abstract #ASH2024ASH_7234;    
    P2
    In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.
  • ||||||||||  bezuclastinib (PLX9486) / Cogent Biosci
    Trial completion date, Trial primary completion date:  CGT9486-20-201: (Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis (clinicaltrials.gov) -  Oct 15, 2024   
    P2,  N=140, Recruiting, 
    Based on a composite of safety/tolerability, efficacy, and pharmacokinetics, 150 mg daily has been chosen as the recommended dose. Trial completion date: Sep 2025 --> Jul 2026 | Trial primary completion date: Jan 2025 --> Jul 2025
  • ||||||||||  Review, Journal:  Systemic Mastocytosis: State of the Art. (Pubmed Central) -  Sep 21, 2024   
    Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions...The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.
  • ||||||||||  Review, Journal, Metastases:  Management of Advanced Systemic Mastocytosis: Clinical Challenges. (Pubmed Central) -  Sep 16, 2024   
    Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib...In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM.
  • ||||||||||  Managing Systemic Mastocytosis (Level 3, 370 AD) -  Jul 5, 2024 - Abstract #SOHO2024SOHO_23;    
    P2, P2/3
    Avapritinib is an oral, highly selective inhibitor of KIT D816V.8 The multi-center phase 1 EXPLORER trial accrued 69 patients in dose escalation and expansion cohorts.9 The ORR was 75%, with a 36% complete remission rate with full or partial hematologic recovery...Imatinib lacks activity against KIT D816V but was approved by the FDA almost two decades ago for adult patients with ASM without the KIT D816V mutation or with unknown KIT mutational status...Elenestinib (HARBOR [NCT04910685] and bezuclastinib (SUMMIT) [NCT05186753]) have also entered clinical trial testing in ISM/ SSM patients with TSS as the primary endpoint...Interrogating the dynamic clonal landscape responsible for clinical progression under the pressure of KIT inhibition is a major translational focus. In addition, the role and timing of hematopoietic stem cell transplantation in the era of KIT inhibition has not been well defined and warrants multi-center collaboration.
  • ||||||||||  bezuclastinib (PLX9486) / Cogent Biosci
    Enrollment open, Combination therapy, Monotherapy:  SARC044: A Phase II Trial of Bezuclastinib in Combination With Sunitinib in Patients With GIST (clinicaltrials.gov) -  Jun 25, 2024   
    P2,  N=40, Recruiting, 
    In addition, the role and timing of hematopoietic stem cell transplantation in the era of KIT inhibition has not been well defined and warrants multi-center collaboration. Not yet recruiting --> Recruiting
  • ||||||||||  bezuclastinib (PLX9486) / Cogent Biosci
    Trial completion date, Trial primary completion date, Combination therapy, Monotherapy:  SARC044: A Phase II Trial of Bezuclastinib in Combination With Sunitinib in Patients With GIST (clinicaltrials.gov) -  May 29, 2024   
    P2,  N=40, Not yet recruiting, 
    Not yet recruiting --> Recruiting Trial completion date: Mar 2027 --> Jun 2027 | Trial primary completion date: Mar 2026 --> Jun 2026
  • ||||||||||  Journal, Stroma:  KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. (Pubmed Central) -  Mar 11, 2024   
    Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA...However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.
  • ||||||||||  ACTR707 / Cogent Biosci, Rituxan (rituximab) / Biogen, Zenyaku Holdings, Roche
    P1 data, Journal, Combination therapy, IO biomarker:  Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B-Cell Lymphoma. (Pubmed Central) -  Feb 5, 2024   
    The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that could potentially be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in employing similar novel approaches of antibody-coupled T-cell activation.
  • ||||||||||  Rydapt (midostaurin) / Novartis, bezuclastinib (PLX9486) / Cogent Biosci, Ayvakit (avapritinib) / Blueprint Medicines
    Review, Journal, Metastases:  Recent Advances in the Therapeutic Management of Advanced Systemic Mastocytosis. (Pubmed Central) -  Jan 11, 2024   
    This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease.
  • ||||||||||  BOXR1030 / Sotio
    Trial completion date, Trial primary completion date:  DUET-1: BOXR1030 T Cells in Subjects With Advanced GPC3-Positive Solid Tumors (clinicaltrials.gov) -  Jan 11, 2024   
    P1/2,  N=110, Recruiting, 
    This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease. Trial completion date: Jul 2039 --> Dec 2041 | Trial primary completion date: Jul 2024 --> Apr 2026
  • ||||||||||  bomedemstat (MK-3543) / Merck (MSD), rusfertide (PTG-300) / Protagonist Therap, bezuclastinib (PLX9486) / Cogent Biosci
    634. Myeloproliferative Syndromes - Clinical and Epidemiological - Treatment and Outcomes in MPNs (Ballroom 20CD (San Diego Convention Center)) -  Nov 3, 2023 - Abstract #ASH2023ASH_4867;    
    In mastocytosis, the KIT inhibitor bezuclastinib shows efficacy and safety in patients with indolent mastocytosis. In myeloid neoplasms with eosinophilia, a custom NGS panel is used to explore the molecular landscape in patients negative for tyrosine kinase fusion genes, identifying recurrent JAK/STAT mutations associated with response to JAK inhibitors.
  • ||||||||||  Review, Journal:  Systemic mastocytosis: 2023 update on diagnosis and management in adults. (Pubmed Central) -  Oct 22, 2023   
    The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.
  • ||||||||||  Current and Emergent Therapies for Systemic Mastocytosis (Level 3, Room 332C) -  Jun 21, 2023 - Abstract #SOHO2023SOHO_22;    
    A very rare variant of SM, seen across its subtypes, is well-differentiated SM (WDSM), characterized by rounded instead of spindled MCs, lack of CD2/25 expression, lack of KIT D816V and responsiveness to imatinib.16 KIT Inhibitors In recent years, the advent of targeted therapy in the form of smallmolecule KIT inhibitors has transformed the management of SM...Subsequent analyses revealed 2 predictors of inferior survival on midostaurin: the presence of S/A/R mutations and a <25% reduction in KIT D816V VAF.19 A more recent registry-based analysis has demonstrated superior outcomes with midostaurin therapy of AdvSM as compared to cladribine.20 Avapritinib Avapritinib is a highly potent (IC50 0.27 nM) and selective inhibitor of KIT D816V and similar mutations.21 It was approved for the treatment of AdvSM (ASM, SM-AHN and MCL) by the FDA on June 16, 2021 at a starting dose of 200 mg daily and for the treatment of ISM on May 22, 2023 at a starting dose of 25 mg daily...Bezuclastinib Bezuclastinib (formerly CGT-9486), like avapritinib, is a highly selective and potent inhibitor of mutant KIT (KIT D816V and similar), but only minimally penetrates the BBB and largely spares closely related kinases, suggesting that it could cause less off-target toxicity than avapritinib (at the higher doses of the latter used in AdvSM).28 It is being studied in patients with advanced SM in the APEX trial and in patients with non-advanced SM (both ISM and SSM) in the SUMMIT trial...Elenestinib Elenestinib, formerly BLU-263, is another potent and selective inhibitor of KIT D816V and similar mutations that is currently being studied in patients with ISM in the HARBOR trial and patients with AdvSM in the AZURE trial that also features combination therapy for patients with SM-AHN. Thus far, the only publicly available data on elenestinib is in healthy volunteers.29 Acknowledgments This work was supported, in part, by the MD Anderson Cancer Center Support Grant P30 CA016672 from the National Cancer Institute (National Institutes of Health).