Imbruvica (ibrutinib)

P2, N=75, Active, not recruiting, Fondazione Italiana Linfomi - ETS | Recruiting --> Active, not recruiting

P2, N=40, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

P1/2, N=38, Completed, Prof. Dr. Clemens Schmitt | Active, not recruiting --> Completed | Trial primary completion date: Jun 2024 --> Nov 2024

P1, N=25, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=12, Completed, Bnai Zion Medical Center | Active, not recruiting --> Completed

P1, N=20, Completed, University Hospital Tuebingen | Active, not recruiting --> Completed

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions...With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care...For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.

Background : Maintenance therapy with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib following ibrutinib-containing chemoimmunotherapy with or without high-dose chemotherapy and autologous stem cell rescue (HDT/ASCR) in younger patients (pts) with mantle cell lymphoma (MCL) has demonstrated superior efficacy over standard chemoimmunotherapy with ASCR (Dreyling et al...Concurrent maintenance with rituximab was not used...At 2 years, the PFS rate (95% confidence interval) was 73.5% (35.9, 91.1) in the overall study population, 37.5% (1.1, 80.8) in pts with MRD+, and 88.9% (43.3, 98.4) in pts with MRD-U (MRD based on status at Day 100).Conclusions : Acalabrutinib demonstrated a tolerable safety profile and promising results in maintaining MRD-U, supporting the use of acalabrutinib as maintenance therapy post-HDT/ASCR in pts with MCL. Given the early study closure, the limited sample size, and the need for longer follow-up for PFS, additional investigations may provide further insights into the role of BTKi maintenance in the post-HDT/ASCR setting.

Base substitution or indel variants were detected in TP53 (28% of cases), KMT2D (25%), CREBBP (14%), EZH2 (8%), MYD88 (8%), TNFRSF14 (8%), ATM (8%), NOTCH1 (7%), ARID1A (6%), B2M (6%), TNFAIP3 (6%), PIM1 (4%), CD79B (3%), BTK (2%, 97% of which were C481X ibrutinib resistance mutations in cases of CLL), MEF2B (2%), BCL2 (1%), and PLCG2 (1%)...Overall, 75% of FLs harbored a canonical IGH : : BCL2 rearrangement and 86% of MCLs harbored a canonical IGH : : CCND1 rearrangement.Conclusions : This analysis of 3,692 samples demonstrated that the F1H assay platform reliably detects a broad landscape of genomic alterations across a range of mature B-cell lymphoma/leukemia subtypes. By detecting all classes of genomic alterations in a single sequencing reaction, F1H provides an important advantage over single-gene and small-panel molecular tests in an era when the diagnosis, prognosis, and treatment of hematological malignancies increasingly rely on assessing the presence, as well as the absence, of numerous genomic alterations.

P1/2, N=34, Active, not recruiting, US Oncology Research | N=26 --> 34 | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

P1, N=45, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2026 --> Apr 2025 | Trial primary completion date: Nov 2024 --> Apr 2025

P3, N=700, Recruiting, Janssen Research & Development, LLC | Enrolling by invitation --> Recruiting

Additionally, high ZAP-70 expression was linked to less cell death in the spleen. Overall, our study enhances understanding of CLL genetics and patient response to ibrutinib and provides a framework applicable to the study of similar drugs.

The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. While further investigation is required, this analysis supports the potential use and further exploration of Bruton tyrosine kinase inhibitors to treat PN symptoms in patients with WM. ClinicalTrials.gov: NCT03053440.

P2, N=622, Recruiting, Genmab | Trial completion date: Nov 2032 --> Jun 2031 | Trial primary completion date: Nov 2032 --> Jun 2031

Oral health care providers should include CLL in the differential diagnosis for multiple erythematous papules of the palatal mucosa, particularly in the presence of absolute lymphocytosis. Early recognition of oral manifestations associated with CLL can prompt a timely referral.

The topical application of the drug successfully reduced irritation and toxicity in the skin, and the drug was shown to successfully permeate the stratum corneum and reach the viable skin layers in therapeutic concentrations. Overall, our data encourage the topical application of IBR to treat melanoma, paving the way for future studies in this theme.

Lasalocid-A exhibited strong antitumor efficacy in xenograft mouse models, induced disease remission in ibrutinib-resistant lymphomas, and showed synergistic activity with the BCL2 inhibitor venetoclax. This study highlights the potential of inducing MYD88 L265P degradation using small molecules, offering promising strategies for treating lymphomas that harbor the MYD88 L265P mutation.

Introduction : The combination of venetoclax, the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing at approximately 230 study sites in 20 countries, including 50 sites in the US, 6 in Brazil, and 15 in Canada.

Emerging long-term data from the cBTKi pivotal trials demonstrated that only a minority of pts can remain on Tx long-term (e.g. 42% of pts were still on ibrutinib [Ibr] at 89-months follow-up [FU] in the RESONATE-2 trial, with 24% having discontinued due to an AE; Barr et al...Pts (aged ≥18 years) are eligible to enroll if they have received ≥6 months of a cBTKi (Ibr, acalabrutinib [Acala], or zanubrutinib [Zanu]) for 1L Tx of CLL and are on a stable dose with a partial response (PR) or complete response (CR), per International Workshop on CLL criteria...Approximately 100 pts are planned for enrollment at around 28 sites in the US. The study is actively recruiting.

Clinical trials that studied the combination of the first generation BTKi ibrutinib and V have shown the feasibility and efficacy of the regimen. Given the favorable safety profile and sustained efficacy of acalabrutinib, combination regimens with venetoclax without (AV) or with obinutuzumab [O] (AVO) have been studied in the first line setting, and favorable efficacy and safety have been reported...Patients with significant cardiovascular disease, absorption issues, active bleeding or history of bleeding diathesis or required/currently receiving anticoagulation with warfarin or equivalent vitamin K antagonists were excluded...Clinical responses including uMRD4 at the end of treatment and the safety profile will be assessed. The trial is actively enrolling at Fred Hutchinson Cancer Center/University of Washington.

P1/2, N=23, Active, not recruiting, Joshua Brody | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Nov 2026

However, compared to MyD88wt counterparts, MyD88D162E BMDMs had increased oxidative stress and dysfunctional mitochondria, along with reduced prosurvival Bcl-xL and BTK expression, rendering cells more prone to apoptosis, exacerbated by ibrutinib treatment...These findings underscore the importance of MyD88wt signaling for NF-κB activation, protecting against macrophage premature apoptosis at resting state. Targeting MyD88 quantity rather than just its signaling could be a promising strategy for MyD88-driven lymphoma treatment.

The study concludes that metformin effectively mitigates ibrutinib-induced cardiotoxicity, including ventricular arrhythmia and cardiac dysfunction, by enhancing AMPK and PI3K-AKT pathway activity. These findings suggest that metformin holds potential as a therapeutic strategy to protect against the adverse cardiac effects associated with ibrutinib treatment, offering a promising approach for improving the cardiovascular safety of patients undergoing therapy for B cell cancers.

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

Research has shown that Bruton's tyrosine kinase (BTK) is a critical regulator of the NLRP3 inflammasome and that the pharmacological inhibition of BTK using the FDA-approved inhibitor ibrutinib diminishes NLRP3-dependent inflammatory response...In our drug discovery efforts, we identified 5,6,7,8-tetrahydropteridines as underutilized scaffolds in medicinal chemistry. We report the synthesis of 5,6,7,8-tetrahydropteridines with potential as anti-inflammatory compounds.

P2, N=15, Active, not recruiting, Bnai Zion Medical Center | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2024 --> Dec 2024

Introduction – We previously reported the efficacy and safety results of a combination of ibrutinib with rituximab in patients (pts) with mantle cell lymphoma (MCL) ≥ 65 years. Conclusions – Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL. Randomized studies are needed to confirm whether this regimen can be the new first line standard treatment for older MCL patients.

The combination of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, the BCL-2 inhibitor venetoclax (V), and the anti-CD20 monoclonal antibody (mAb) obinutuzumab (O) has demonstrated safety and efficacy in R/R and TN MCL (Le Gouill, Blood 2021). Conclusions : AVO is safe and active in pts with R/R and TP53-aberrant/transplant ineligible TN MCL. Preliminary efficacy and feasibility of an MRD-guided treatment approach is encouraging in this high-risk TN cohort B. Our data supports further investigation of a targeted triplet approach, and the phase II TN transplant eligible and TP53 wild type cohort is enrolling based on demonstrated safety and efficacy in cohort B. Updated results will be presented at the meeting.

Zanubrutinib is a second-generation BTKi with superior PFS and safety compared with ibrutinib (Brown NEJM 2023). Retreatment with zanubrutinib-venetoclax was also well-tolerated and effective. A phase 2 trial of BOVen with ΔMRD400-directed treatment duration is ongoing.

We selected 108 CLL patient samples with genetic annotation and exposed them ex-vivo to small-molecule inhibitors used clinically (ibrutinib/BTKi, duvelisib/PI3Ki, trametinib/MEKi, everolimus/mTORi, selinexor/XPO1i) or targeting key signaling pathways (compound 26/TLRi, MK2206/AKTi, nutlin-3a/MDM2i, IBET872/BETi) for 48h. In conclusion, the addition of targeted pathway perturbations to the GEP of primary CLL samples can greatly enhance the potential for molecular and functional classification of disease and subgroups. Our study provides a blueprint to use perturbed omics profiling and interaction testing to link disease drivers to pathway activation and function.

Fixed-duration ViPOR-P x 6C without maintenance resulted in durable CRs, especially in pts with non-GCB DLBCL by IHC and ABC DLBCL by RNA-seq, including refractory and post-CAR-T pts. Molecular and MRD analyses are ongoing, and enrollment continues to assess whether ViPOR-P improves CR rate compared to ViPOR alone in R/R non-GCB DLBCL.

ViPOR with a 12d VEN ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia. Enrollment continues to better define the response and durability of ViPOR in MCL.

Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton's tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439)...Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Introduction : Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented.

In preclinical studies, lenalidomide has been shown to induce cytotoxicity in ABC DLBCL cells by inhibiting NF-κB signaling and a synergistic effect is seen when B-cell receptor signaling is inhibited by the BTK inhibitor ibrutinib. Similar efficacy was observed across DLBCL subtypes; ORR was numerically higher in the ABC subtype. Further molecular analysis is ongoing.

We present the 6-year update of a phase 2 study evaluating the combination of obinutuzumab and idelalisib in relapse/refractory Waldenstrom macroglobulinemia. Moreover, ibrutinib remains an effective treatment after this combination. This study was registered on the clinicaltrial.gov web (NCT02962401, November 9, 2016).

P2, N=622, Recruiting, Genmab | Trial completion date: Jun 2031 --> Nov 2032 | Trial primary completion date: Jun 2031 --> Nov 2032

P2, N=100, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Jun 2030

P2, N=112, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting | N=200 --> 112

P2, N=29, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Jun 2026 --> Dec 2025

P2, N=120, Active, not recruiting, French Innovative Leukemia Organisation | Trial completion date: Jun 2026 --> Jan 2025