Imbruvica (ibrutinib)

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

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). 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.

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.

Zanubrutinib is a second-generation BTKi with superior PFS and safety compared with ibrutinib (Brown NEJM 2023). Five-year follow up of the BOVen regimen demonstrates frequent uMRD4 in PB (96%) and BM (92%), and uMRD4 was durable with a median MRD4-free survival of 34 mo. 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.

ViPOR-P is safe without notable additional toxicity, especially neutropenia and neuropathy, compared to ViPOR, and DL3 was identified as the RP2D. Most AEs were hematologic and manageable with G-CSF with rare febrile neutropenia observed. 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.

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)... High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles.

Fixed-duration ViPOR x 6C without maintenance achieved CR in 100% and uMRD in 97% of MCL pts, with ongoing CR in 95% and 73% of TN and R/R pts, respectively, and only 1 R/R pt receiving consolidative allo-HSCT. This includes blastoid, TP53 mutated, and post-BTKi high-risk subsets. ViPOR with a 12d VEN ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia.

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). We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

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. The results of the BGB-3111-110 study demonstrated that the RP2D of zanubrutinib 160 mg twice daily plus lenalidomide 25 mg once daily had a manageable safety profile and promising efficacy in patients with R/R DLBCL. 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

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

A 75-year-old man presented with uveitis masquerade syndrome while undergoing treatment for MCL with rituximab-bendamustine. During the study course, CD5 and CD20 positive cells were identified in the anterior chamber of the eyes via flow cytometry, which was consistent with the pathological findings of biopsies. Ibrutinib may improve recurrent MCL intraocular lesions.

P1, N=14, Active, not recruiting, Alliance Foundation Trials, LLC. | Trial primary completion date: Mar 2025 --> Sep 2024

Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

P2, N=200, Recruiting, Incyte Corporation | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

P2, N=120, Not yet recruiting, National Cancer Institute (NCI)

Hairy cell leukemia is an uncommon B-cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. Only one patient in our cohort passed away due to infection. Estimated 10-year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

P2, N=36, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

Tailored chemo-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different response spectra.

However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). Our findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL. PROSPERO CRD42022304330.

P=N/A, N=256, Recruiting, Janssen Cilag S.A.S. | Trial completion date: Dec 2026 --> Jun 2027

P2, N=64, Completed, Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea | Unknown status --> Completed

This large real-world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double-hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.

P1/2, N=225, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2027 --> May 2028

P2, N=35, Active, not recruiting, Mayo Clinic | Trial primary completion date: Dec 2024 --> Dec 2023

Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy.

P1/2, N=102, Completed, Oncternal Therapeutics, Inc | Active, not recruiting --> Completed

P2, N=18, Active, not recruiting, Institute of Hematology & Blood Diseases Hospital, China | Recruiting --> Active, not recruiting

Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.

Furthermore, many mutations discovered in PLCγ2 have been linked to the development of complex immune disorders as well as resistance to ibrutinib treatment in chronic lymphocytic leukaemia...These data, combined with the structural insights, suggest that the PLCγ2 P522R variant has subtle, localised structural changes that do not directly affect the PLC activity by compromising autoinhibition, as determined for PLCγ2 M1141K. It is also likely that in contrast to the PLCγ2 M1141K, the functional impact of the P522R substitution completely depends on further interactions with upstream kinases and other regulatory proteins in a relevant cellular context, where changes in the PLCγ2 P522R variant could facilitate processes such as phosphorylation and protein-protein interactions.