spebrutinib (CC-292) / BMS - LARVOL DELTA

Understanding Resistance Mechanisms and Growth Kinetics of CLL Treated with Covalent and Non-Covalent BTK Inhibitors (ASH 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."

IO biomarker • Chronic Lymphocytic Leukemia • Oncology • BIRC3 • MCL1 • TP53

Outcomes and Treatment Sequences of Therapies with BCL2- and BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL): An Analysis of Patient Data within the German CLL Study Group (GCLLSG) Registry (ASH 2023) - "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."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • IGH • TP53

COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale. (PubMed, Nat Commun) - "We validated COOKIE-Pro using BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and unreported off-targets. This approach successfully generated thousands of kinetic profiles, enabling the quantitative decoupling of intrinsic chemical reactivity from binding affinity at scale and validating the method's broad applicability. By providing a comprehensive view of covalent inhibitor binding across the proteome, COOKIE-Pro represents a powerful tool for optimizing the potency and selectivity of covalent drugs during preclinical development."

Journal

COOKIE-Pro: Covalent Inhibitor Binding Kinetics Profiling on the Proteome Scale. (PubMed, bioRxiv) - "We validated COOKIE-Pro using the BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and novel off-targets. We further demonstrate that COOKIE-Pro is compatible with streamlined cysteine activity-based protein profiling (SLC-ABPP) datasets, enabling efficient conversion of competition ratios to meaningful kinetic parameters. By providing a comprehensive view of covalent inhibitor binding across the proteome, COOKIE-Pro represents a powerful new tool for optimizing the potency and selectivity of covalent drugs during preclinical development."

Journal

Establishing preclinical models for clear cell sarcoma of soft tissue. (PubMed, Front Oncol) - "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."

Journal • Preclinical • Ewing Sarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • ATF1 • EWSR1 • FLI1

System biology based drug repositioning approach identifies drug candidates for pancreatic ductal adenocarcinoma (SITC 2024) - "Employing our systematic drug repositioning approach, we identified AVL-292 and MK-5108 as promising candidates for PDAC treatment. Additional experimental validation confirmed that these compounds significantly inhibited cell motility, suggesting potential therapeutic benefits. Conclusions Our study demonstrates the feasibility and efficacy of a network-based drug repositioning approach in identifying potential drugs for the treatment of PDAC."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1 | N=174 | Terminated | Sponsor: Celgene | Active, not recruiting ➔ Terminated; Replaced with another clinical trial.

Trial termination • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases. (PubMed, J Med Chem) - "In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteoclastogenesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs."

Journal • Dental Disorders • Immunology • Inflammation • Periodontitis • Targeted Protein Degradation • NFATC1 • PLCG2

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1 | N=174 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b ➔ P1 | Trial completion date: Oct 2023 ➔ Jan 2024 | Trial primary completion date: Oct 2023 ➔ Jan 2024

Phase classification • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

Influence of Bruton's Tyrosine Kinase (BTK) on Epithelial-Mesenchymal Transition (EMT) Processes and Cancer Stem Cell (CSC) Enrichment in Head and Neck Squamous Cell Carcinoma (HNSCC). (PubMed, Int J Mol Sci) - "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."

Cancer stem • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ALDH1A1 • BTK • IFNG • IL6 • RELA • TNFA

Novel agents in relapsed/refractory diffuse large B-cell lymphoma (ICML 2023) - "In recent years, numerous agents have been approved specifically for patients with DLBCL (RED) including tafasitamab, loncastuximab tesirine, polatuzumab vedotin, selinexor, rituximab, and pembrolizumab (for patients with Primary Mediastinal B-cell lymphoma)...Significant grade 3-4 toxicities were neutropenia and thrombocytopenia with 48.6% of patients requiring dose modifications, and 22.9% discontinuing treatment for toxicity.12 Ongoing and planned trials with loncastuximab include a phase III trial with rituximab, gemcitabine, and oxaliplatin (R-GemOx) (Tables 1 and 3)...Encouraging clinical activity, without unanticipated toxicities was observed when polatuzumab was combined with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) with an ORR of 89% (CR 61%).24 Combination of polatuzumab with lenalidomide and rituximab (R2) in 49 patients demonstrated an ORR of 35% (CR 29%), with median DOR, PFS, and OS of 8.1, 6.3, and 10.9 months, respectively...One notable..."

IO biomarker • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Mediastinal B Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CARD11 • CD79B • CDKN1A • CRBN • CTLA4 • EZH2 • IKZF1 • IRAK4 • LYN • MALT1 • MCT1 • MYC • MYD88 • NF-κβ • PD-L1 • ROR1 • SIRPA • SYK • XPO1

Reactive intermediates formation and bioactivation pathways of spebrutinib revealed by LC-MS/MS: In vitro and in silico metabolic study. (PubMed, Heliyon) - "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."

Journal • Preclinical • Hematological Malignancies • Lymphoma • Oncology

COMPREHENSIVE MOLECULAR SUBTYPING OF DIFFUSE LARGE B-CELL LYMPHOMA CELL LINES AND ASSOCIATION WITH TAFASITAMAB ACTIVITY (EHA 2023) - P1b/2a, P2, P3 | "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..."

IO biomarker • Preclinical • Bone Marrow Transplantation • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Transplantation • TP53

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1b | N=174 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Apr 2023 ➔ Jul 2023 | Trial primary completion date: Apr 2023 ➔ Jul 2023

Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • CD20

Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia. (PubMed, Bioorg Chem) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Potency and Selectivity of BTK Inhibitors in Clinical Development for B-Cell Malignancies (SOHO 2019) - "Ibrutinib, zanubrutinib, and spebrutinib had EC50 values <1 μM in Jurkat T cells.Conclusions BTK inhibitors showed differing potency in biochemical assays, but differences were partly lost in cellular assays, particularly in hWB. Based on kinase selectivity profiles, acalabrutinib and tirabrutinib had the highest kinase selectivity.Funding Acerta Pharma, a member of the AstraZeneca Group."

Clinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

A Rapid and Sensitive Liquid Chromatography-Tandem Mass Spectrometry Bioanalytical Method for the Quantification of Encorafenib and Binimetinib as a First-Line Treatment for Advanced (Unresectable or Metastatic) Melanoma-Application to a Pharmacokinetic Study. (PubMed, Molecules) - "Plasma samples were pre-treated using protein precipitation with acetonitrile containing spebrutinib as the internal standard (IS). The AUC for BNB and ENF was found to be 18.16 ± 1.31 and 36.52 ± 3.92 µg/mL.h, respectively. On the other hand, the elimination half-life (t) parameters for BNB and ENF in the rat plasma were found to be 3.39 ± 0.43 h and 2.48 ± 0.24 h, and these results are consistent with previously reported values."

Journal • Metastases • PK/PD data • Melanoma • Oncology • Solid Tumor

BTK Isoforms p80 and p65 Are Expressed in Head and Neck Squamous Cell Carcinoma (HNSCC) and Involved in Tumor Progression. (PubMed, Cancers (Basel)) - "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."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BTK • RELA

CC-122 DLBCL-001: Phase Ib Study of CC-122 Plus Rituximab in Patients with Chemo-Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (ASH 2017) - P1a/1b,P1b; "...CC-122 has shown promising phase I clinical activity as a single agent or in combination with obinutuzumab in DLBCL and follicular lymphoma (FL) (NCT01421524 Rasco et al, ASH 2013; NCT02417285 Michot et al, ASH 2016)... Data from this ongoing study suggest that CC-122 is well-tolerated when combined with rituximab. Promising activity was observed accross DLBCL cell-of-origin in this chemo-refractory patient population at the recommended phase II dose of 3.0 mg/day using CC-122 formulated capsule. Gene expression classifier based on tumor microenvironment content shows a trend towards predicting deeper and durable responses."

Adverse events • P1 data • Biosimilar • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Indolent Lymphoma • Pain

Development of novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors with potent in vivo anti-hematological malignancies effects. (PubMed, Eur J Med Chem) - "Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC values of 47 and 12 nM, respectively, which were superior to spebrutinib (BTK IC = 54 nM) and sorafenib (FLT3 IC = 33 nM). Importantly, RSH-7 demonstrated highly efficacious and well-tolerated in jeko-1 (50 mg/kg, TGI = 79.78%) and MV4-11 (20 mg/kg, TGI = 94.84%) xenograft models. These findings indicated that RSH-7 may be a promising lead compound for the treatment of hematological malignancies."

Journal • Preclinical • Hematological Disorders • Hematological Malignancies • Oncology • BCL2 • FLT3

Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma. (PubMed, EJHaem) - P1b | "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."

Journal • P1 data • Diffuse Large B Cell Lymphoma • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • CRBN

An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton's Tyrosine Kinase Inhibitor. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "CC-292 was well tolerated when administered to healthy subjects as single oral doses under all conditions. Food intake had no clinically relevant impact on CC-292 pharmacokinetics compared to fasted conditions. Therefore, CC-292 can be administered with or without food. Co-administration of CC-292 with multiple doses of omeprazole (40 mg) decreased the pharmacokinetic exposure of CC-292. However, the effect was not clinically relevant."

Journal • P1 data

An open-label, phase 1, randomized, three treatments, three-period, crossover, relative bioavailability study of CC-292, a potent and orally available inhibitor of bruton tyrosine kinase. (PubMed, J Clin Pharm Ther) - "For all three formulations, following administration of CC-292 at a dose level of 250 mg under fasted conditions, CC-292 was rapidly absorbed with maximum plasma concentrations (Cmax) occurring at a median of 1.5-1.75 h (Tmax). P22-CAP formulation showed a similar range of Tmax compared to P01-CAP and P22-TAB showed a wider range of Tmax compared to P01-CAP. Comparable or higher Cmax and AUC0-∞ were noted for P22-TAB and P22-CAP formulations as compared to P01-CAP formulation. The relative bioavailability (Frel) of the CC-292 P22-TAB compared to the P01-CAP reference formulation was 1.02, and the relative bioavailability (Frel) of the CC-292 P22-CAP compared to the P01-CAP reference formulation was 1.23. In conclusion, CC-292 was well tolerated when administered as single 250-mg oral doses of P22-TAB, P22-CAP or P01-CAP in the fasted state in this group of healthy subjects. Given that CC-292 has shown favourable safety profiles in the current clinical settings,..."

Journal • P1 data

Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma (clinicaltrials.gov) - P1b; N=174; Active, not recruiting; Sponsor: Celgene; Trial completion date: Nov 2021 ➔ Nov 2022; Trial primary completion date: Nov 2021 ➔ Nov 2022

Clinical • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20

CC-122-DLBCL-001: PHASE IB STUDY OF CC-122 PLUS RITUXIMAB IN PATIENTS WITH CHEMO-REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (EHA 2018) - P1b; "...CC-122 has shown promising activity in combination with obinutuzumab or rituximab in relapsed or refractory DLBCL and follicular lymphoma (FL) (Michot et al, ASH 2017; Ribrag et al, ASH 2017)...Methods CC-122-DLBCL-001 is a phase Ib dose escalation/expansion study of CC-122, CC-223, and CC-292 given orally as doublets and triplets in combination with rituximab in chemo-refractory pts (NCT02031419; Ribrag et al, ASH 2016)... In pts with chemo-refractory DLBCL, CC-122 combined with rituximab demonstrated manageable toxicities, with a low incidence of severe AEs. This combination showed favorable clinical activity and may represent an important treatment option in a difficult to treat pt population. Notably, gene expression classifier positive pts had encouraging clinical activity."

Clinical • P1 data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Indolent Lymphoma