To better understand the impact of the second-generation BTKi acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. Our analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.

P3, N=900, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

P3, N=900, Active, not recruiting, Sanofi | Trial completion date: Apr 2024 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Aug 2024

P2, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=50 --> 32

P2, N=111, Completed, Beijing InnoCare Pharma Tech Co., Ltd. | Active, not recruiting --> Completed

P2, N=47, Completed, Beijing InnoCare Pharma Tech Co., Ltd. | Active, not recruiting --> Completed

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

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

P=N/A, N=152, Completed, French Innovative Leukemia Organisation | Recruiting --> Completed

P2, N=40, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P3, N=2500, Recruiting, Sanofi

Venetoclax was associated with total monthly cost savings versus BTKis, illustrating the economic value of time-limited venetoclax-based regimens in the 2L setting.

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=66, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=112, Recruiting, Guangzhou Lupeng Pharmaceutical Company LTD. | Not yet recruiting --> Recruiting

P3, N=607, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax and obinutuzumab after an optional bendamustine debulking in 45 patients with relapsed/refractory CLL (one patient was excluded from the analysis due to a violation of exclusion criteria). The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. ClinicalTrials.gov Identifier: NCT03787264.

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

P2, N=15, Completed, SCRI Development Innovations, LLC | Active, not recruiting --> Completed | Trial completion date: Aug 2027 --> Apr 2024 | Trial primary completion date: Aug 2027 --> Apr 2024

P2, N=260, Recruiting, Swiss Group for Clinical Cancer Research | Trial primary completion date: Mar 2026 --> Oct 2025

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.

P1, N=12, Recruiting, National Cancer Institute (NCI) | Trial primary completion date: Mar 2024 --> Mar 2025

P2, N=25, Active, not recruiting, Polish Lymphoma Research Group | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2024 --> Jun 2024

P3, N=490, Not yet recruiting, InnoCare Pharma Inc.

P1, N=28, Recruiting, Sanofi | Not yet recruiting --> Recruiting

P3, N=746, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

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.

P1, N=72, Recruiting, Inmagene LLC | Completed --> Recruiting | N=40 --> 72 | Trial completion date: Jan 2023 --> Nov 2024 | Trial primary completion date: Jan 2023 --> May 2024

P1/2, N=27, Not yet recruiting, OHSU Knight Cancer Institute

P2, N=92, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Mar 2028 | Trial primary completion date: Apr 2024 --> Mar 2028

P2, N=40, Not yet recruiting, City of Hope Medical Center | Initiation date: Mar 2024 --> Jun 2024

P2, N=43, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P3, N=250, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

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.

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.

P3, N=468, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2026 --> Mar 2027

P2, N=18, Active, not recruiting, National Cancer Institute (NCI)

P2, N=41, Active, not recruiting, National Cancer Institute (NCI)

P3, N=0, Withdrawn, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | N=200 --> 0 | Not yet recruiting --> Withdrawn

Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142).

P2, N=27, Recruiting, Patrick C. Johnson, MD | Not yet recruiting --> Recruiting | Trial completion date: Sep 2029 --> Mar 2029 | Trial primary completion date: Sep 2024 --> Mar 2025