spebrutinib (CC-292)

All the in-frame fusions are constitutively active. We developed both in vitro and in vivo models of CCSST metastasis based on the CCS292 cell line, which are valuable tools for assessing potential therapeutics for CCSST patients.

P1, N=174, Terminated, Celgene | Active, not recruiting --> Terminated; Replaced with another clinical trial.

P1, N=174, Active, not recruiting, Celgene | Phase classification: P1b --> P1 | Trial completion date: Oct 2023 --> Jan 2024 | Trial primary completion date: Oct 2023 --> Jan 2024

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.

We performed whole exome sequencing on matched tumor and normal samples from 19 CLL patients treated with BTK inhibitors (Ibrutinib, Ibr, 42% (8/19); Acalabrutinib, Acala, 21% (4/19) and Pirtobrutinib, Pirto, 37% (7/19))...The ibr cohort had no prior BTKi therapy whereas 1 patient in the acala cohort had received spebrutinib, another cBTKi...The approach of combining WES data with growth pattern modeling can help unravel the complexities of tumor evolution and drug resistance for the different classes of BTKi. Data on comparative clone growth rates will be presented at the meeting.

Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1 CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC.

Several iminium, 2-iminopyrimidin-5(2H)-one and aldehyde intermediates of SPB were revealed. Acrylamide is identified as a structural alert for toxicity by DEREK report and was found to be involved in the formation of several glycidamide and aldehyde reactive intermediates.

P1b, N=174, Active, not recruiting, Celgene | Trial completion date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2023 --> Jul 2023

Background: Tafasitamab (tafa), an anti-CD19 immunotherapy that enhances antibody dependent cellular cytotoxicity (ADCC) and phagocytosis, achieved a 57.5% objective response rate in combination with lenalidomide in the phase 2 L- MIND trial (NCT02399085), and received accelerated US approval and conditional authorization in Europe for treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant...Sensitivity data on DLBCL cell lines screened against BTK inhibitors (AVL-292, acalabrutinib, ibrutinib) were obtained from the PRISM repurposing dataset... Consistent with L-MIND clinical data, tafa was active in both GCB and non-GCB DLBCL cell lines. Additionally, tafa activity was not associated with a specific molecular subtype or mutations in TP53. Biomarker analyses are ongoing in tafa clinical trials (topMIND [NCT04809467], frontMIND [NCT04824092], firmMIND [NCT05429268]) to confirm these findings and provide further insight into genomic and immune parameters that may play a rolein response to tafa.

A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia...Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.

Together, these data indicate BTK-p80 and BTK-p65 as novel HNSCC-associated oncogenes. Owing to the fact that abundant BTK expression is a characteristic feature of primary and metastatic HNSCC, targeting BTK activity appears as a promising therapeutic option for HNSCC patients.

CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.