P2, N=18, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025
15 hours ago
Trial completion date • Trial primary completion date
P1, N=4, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=12 --> 4 | Trial completion date: Mar 2034 --> Jun 2029 | Trial primary completion date: Mar 2025 --> Jun 2024
15 hours ago
Enrollment closed • Enrollment change • Trial completion date • Trial primary completion date
Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% )...It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.
P2, N=30, Active, not recruiting, Swiss Group for Clinical Cancer Research | Trial completion date: Dec 2028 --> Dec 2026 | Trial primary completion date: Apr 2028 --> Apr 2026
4 days ago
Trial completion date • Trial primary completion date
The covalently bound Ibrutinib molecule, recognized for its ability to inhibit BTK, was used as the query molecule...Covalent docking simulations were applied to the selected small-molecules obtained through text mining from databases. Potent hit molecules capable of inhibiting BTKs through virtual screening algorithms were identified, paving the way for novel therapeutic strategies in the treatment of CLL.
Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.
Moreover, combination of dasatinib with BTK inhibitors (BTKi) (ibrutinib, acalabrutinib or zanubrutinib) significantly decreased E2A-PBX1+/preBCR+ human and murine cell proliferation, reduced PLCG2 and BTK phosphorylation and total protein levels and increased disease-free survival of mice in secondary transplantation assays, reducing particularly CNS-leukemic infiltration. Hence, dasatinib with ibrutinib reduced pPLCG2 and pBTK in primary ALL patient samples, including E2A-PBX1+ ALLs. In summary, genetic depletion and pharmacological inhibition of BTK increase dasatinib effects in human and mouse E2A-PBX1+/preBCR+ ALL in most of performed assays, and the combination of dasatinib and BTKi is very effective in reducing CNS-infiltration of E2A-PBX1+/preBCR+ ALL cells in vivo.
Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases. The combination of NI@I-NPs and chemotherapeutic drugs (doxorubicin and etoposide) extended the median survival of mice with breast cancer brain metastases. Targeting BTB endothelial WNT signaling and tumor pericytes via NI@I-NPs could open the BTB to improve chemotherapeutic efficiency against brain metastases.
14 days ago
Journal
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ICAM1 (Intercellular adhesion molecule 1)
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Imbruvica (ibrutinib) • doxorubicin hydrochloride • etoposide IV
IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.
In vivo studies first revealed that ibrutinib enhances the antitumor effect of 20j without side effects in a DOHH2 xenograft model. This study provided a solid foundation for the future development of a MNK inhibitor for GCB-DLBCL treatment.
16 days ago
Journal
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EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)
Targeting DNMT3A with low-dose decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-mediated metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.
P1, N=16, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
21 days ago
Trial completion date • Trial primary completion date • Combination therapy
Finally, the added value of Orai1 inhibitors in combination with B-CLL drugs (ibrutinib, idelalisib, rituximab, and venetoclax) on B-CLL survival was tested, showing an additive/synergistic effect including in the B-cell cancer lines. To conclude, this study highlights the pathophysiological role of the Ca2+ channel Orai1 in B-cell cancers, and pave the way for the use of ORAI1 modulators as a plausible therapeutic strategy.
The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.
22 days ago
Review • Journal • IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion.
Time-to-event analyses showed that MCL international prognostic index (MIPI) high-risk category and higher STAT5 response were predictors of shorter PFS and OS whilst MIPI high-risk category and high SYK response predicted shorter OS. In conclusion, we identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib, thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL.
25 days ago
Journal
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PLCG2 (Phospholipase C Gamma 2) • SYK (Spleen tyrosine kinase)
In parallel to the demonstration of benefit using combination therapy with rituximab plus high-dose cytarabine (R-AraC) as well as dose intensive therapy-autologous stem cell transplantation (DIT-ASCT) consolidation and maintenance, it became clear over the last 2 decades that MCL is a highly heterogenous disease at the molecular level, explaining differences observed in clinical behavior and response to therapy...The era of integrating novel agents into our prior standard of care (SOC) has begun with a confirmed benefit, for example, ibrutinib (Ib) in the TRIANGLE study, defining the first new potential SOC in younger patients in over 30 years...Taking into account the biological diversity of MCL is now feasible in routine clinical practice and has already helped recognize what not to do for HR patients (i.e., avoid intensive induction chemotherapy and/or ASCT for p53 mutated patients) as well as identify promising novel options. Ongoing and future work will help expand on these dedicated approaches, to further improve the management and outcomes of all MCL patients.
In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment.
1 month ago
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • NFKBIE (NFKB Inhibitor Epsilon)
P2, N=320, Recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025
1 month ago
Trial completion date • Trial primary completion date • Combination therapy
P2, N=190, Terminated, Swiss Group for Clinical Cancer Research | Trial completion date: Dec 2029 --> Jul 2023 | Active, not recruiting --> Terminated; The premature termination is based on the decision by the SAKK board on November 14, 2020 due to the lack of further financial support for the follow up period.
1 month ago
Trial completion date • Trial termination • Metastases
Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.
No additional safety concerns than those already mentioned in previous studies could be noticed.Trial registration ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 - Retrospectively registered.
Clinically significant findings, such as ABC COO (n = 16), TP53 loss (n = 13), DHITsig+ (n = 6), and CARD11 mutations associated with ibrutinib resistance (n = 3), were identified in 33 samples... Our results show the clinical utility and acceptable TAT of using a comprehensive WES and RNA-seq assay on a cohort of lymphoma patients. The produced BostonGene Tumor PortraitTM test reports included findings on significant alterations, LymphGen and LME subtypes, COOs, and potential clinical trial matches. These robust findings, coupled with the rapid TAT, demonstrate the feasibility of using integrated WES and RNA-seq to guide clinical decision-making in lymphoma patients.
1 month ago
Clinical • Whole exome sequencing
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TP53 (Tumor protein P53) • CARD11 (Caspase Recruitment Domain Family Member 11)
P2, N=5, Active, not recruiting, University of California, San Diego | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: Jan 2024 --> Jan 2025
1 month ago
Trial completion date • Trial primary completion date • Combination therapy • IO biomarker • Metastases