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DRUG CLASS:

Casein kinase I epsilon inhibitor

1m
Treatment of Relapsed/Refractory CLL Patients With PI3Kδ Inhibitor and Anti-CD20 Antibody Rapidly Decreases Tumor Burden but Could Induce Resistance. (PubMed, Am J Hematol)
The clinical trial utilized 1)a therapeutic anti-CD20 monoclonal antibody (mAb), ublituximab, which destroys CLL cells by an antibody-dependent cellular phagocytosis (ADCP) mechanism; 2)a B cell receptor (BCR) signaling inhibitor, umbralisib, which blocks PI3Kẟ; 3)and an anti-apoptosis inhibitor, venetoclax, which blocks cell survival promoted by BCL-2 that stops mitochondria from initiating apoptosis. Standard high dose (375 mg/m2) anti-CD20 antibody treatment significantly decreased CLL surface CD20 levels, potentially limiting treatment efficacy. Anti-CD20 antibody plus B cell receptor signaling inhibition reduced CLL cell counts and lymph node tumors, enabling BCL-2 inhibitor treatment to avoid tumor lysis syndrome.
Journal
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PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
Venclexta (venetoclax) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
4ms
Acalabrutinib, Umbralisib and Ublituximab Regimen (AU2) Demonstrates High Response Rate and Undetectable Molecular Minimal Residual Disease (MRD) in Patients (pts) with De Novo Mantle Cell Lymphoma (MCL) (ASH 2024)
Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.
Clinical • IO biomarker • Minimal residual disease
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TP53 (Tumor protein P53)
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TP53 mutation
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clonoSEQ
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Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
4ms
Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov)
P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026
Trial primary completion date
|
Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
5ms
Acalabrutinib, Umbralisib, and Ublituximab (AU2) In Relapsed and Untreated CLL (clinicaltrials.gov)
P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Jan 2025 --> Dec 2023
Trial primary completion date
|
Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
6ms
TLB-001 safety and tolerability study (ACTRN12624000813583)
P1, N=64, Recruiting, Tianli Biotech Pty Ltd | Not yet recruiting --> Recruiting
Enrollment open • Trial initiation date
8ms
Enrollment closed
|
CD4 (CD4 Molecule)
|
lenalidomide • doxorubicin hydrochloride • Gazyva (obinutuzumab) • cyclophosphamide • vincristine • Ukoniq (umbralisib) • Belrapzo (bendamustine RTD)
8ms
Evaluate the Efficacy and Safety of TGR-1202 in Participants With Chronic Lymphocytic Leukemia Who Are Intolerant to Prior Therapy (clinicaltrials.gov)
P2, N=51, Terminated, TG Therapeutics, Inc. | Completed --> Terminated; (Strategic/Business Decision)
Trial termination
|
Ukoniq (umbralisib)
9ms
TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea (clinicaltrials.gov)
P1, N=60, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> May 2024
Trial completion • Trial completion date
|
Jakafi (ruxolitinib) • Ukoniq (umbralisib) • hydroxyurea
10ms
A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL (clinicaltrials.gov)
P1, N=45, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Aug 2023
Trial completion • Trial completion date • Combination therapy
|
Imbruvica (ibrutinib) • Ukoniq (umbralisib)
10ms
Umbralisib and Rituximab as Initial Therapy for Patients With Follicular Lymphoma and Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=18, Terminated, Massachusetts General Hospital | N=41 --> 18 | Trial completion date: Nov 2024 --> May 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2023 --> May 2024; Umbralisib development terminated; closed to accrual 8/29/2022
Enrollment change • Trial completion date • Trial termination • Trial primary completion date
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Rituxan (rituximab) • Ukoniq (umbralisib)
10ms
Trial termination • Combination therapy
|
Gazyva (obinutuzumab) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • Leukeran (chlorambucil)
11ms
SWOG S1608: Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma (clinicaltrials.gov)
P2, N=95, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2025
Trial completion date • Trial primary completion date
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CD4 (CD4 Molecule)
|
lenalidomide • doxorubicin hydrochloride • Gazyva (obinutuzumab) • cyclophosphamide • vincristine • Ukoniq (umbralisib) • Belrapzo (bendamustine RTD)
1year
Combination of Pembrolizumab With TGR-1202 in Patients With Relapsed/Refractory CLL and B-cell NHL (clinicaltrials.gov)
P1, N=20, Active, not recruiting, University of Chicago | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2023 --> Dec 2027
Trial completion date • Trial primary completion date
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Keytruda (pembrolizumab) • Ukoniq (umbralisib)
1year
A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL (clinicaltrials.gov)
P1, N=45, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2023 --> Mar 2024
Trial completion date • Combination therapy
|
Imbruvica (ibrutinib) • Ukoniq (umbralisib)
over1year
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=12, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2023 --> Sep 2025
Trial completion date • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
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Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
A Phase 2 Study of Acalabrutinib, Umbralisib, and Ublituximab (AU2) in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (ASH 2023)
Immune-related adverse events were frequently observed and required dose reduction of umbralisib in 38% of the patients but most were then able to stay on therapy. Longer follow-up is required to determine durability of remission off therapy.
P2 data • IO biomarker
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TP53 (Tumor protein P53) • ATM (ATM serine/threonine kinase) • NOTCH1 (Notch 1) • SF3B1 (Splicing Factor 3b Subunit 1) • IGH (Immunoglobulin Heavy Locus) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
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TP53 mutation • ATM mutation • NOTCH1 mutation • SF3B1 mutation • ATM deletion • TS 12
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over1year
UNITY-CLL: Ublituximab + TGR-1202 Compared to Obinutuzumab + Chlorambucil in Patients With Untreated and Previously Treated Chronic Lymphocytic Leukemia (clinicaltrials.gov)
P3, N=603, Completed, TG Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2024 --> Feb 2023 | Trial primary completion date: Nov 2023 --> Feb 2023
Trial completion • Trial completion date • Trial primary completion date
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Gazyva (obinutuzumab) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • Leukeran (chlorambucil)
over1year
Umbralisib and Rituximab as Initial Therapy for Patients With Follicular Lymphoma and Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=41, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2022 --> Nov 2023
Enrollment closed • Trial primary completion date
|
Rituxan (rituximab) • Ukoniq (umbralisib)
over1year
Umbralisib Plus Ublituximab (U2) in Progressive CLL After Novel Therapy (clinicaltrials.gov)
P2, N=1, Terminated, Weill Medical College of Cornell University | N=24 --> 1 | Recruiting --> Terminated; Terminated due to low accrual
Enrollment change • Trial termination
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BCL2 (B-cell CLL/lymphoma 2)
|
Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
almost2years
Tazemetostat in Combination With Umbralisib and Ublituximab for the Treatment Relapsed or Refractory Follicular Lymphoma (clinicaltrials.gov)
P1/2, N=0, Withdrawn, City of Hope Medical Center | N=48 --> 0 | Not yet recruiting --> Withdrawn
Enrollment change • Trial withdrawal • Combination therapy
|
Tazverik (tazemetostat) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
almost2years
Dual inhibition of phosphoinositide 3-kinases delta and gamma reduces chronic B cell activation and autoantibody production in a mouse model of lupus. (PubMed, Front Immunol)
Targeting of PI3Kδ using FDA-approved drugs Idelalisib or Umbralisib has shown efficacy in treatment of multiple B cell malignancies. Duvelisib, an inhibitor targeting both PI3Kδ and PI3Kγ (PI3Kδγi) has also been used for treatment of several leukemias and lymphomas and was suggested to offer potential additional benefits in supressing T cell and inflammatory responses...Kidney pathology was also impacted, with reduced IgG deposition and glomerulonephritis. These results indicate that dual inhibition of PI3Kδ and PI3Kγ can target autoreactive B cells and may have therapeutic benefits in autoantibody-mediated disease.
Preclinical • Journal
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PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • CD86 (CD86 Molecule)
|
Zydelig (idelalisib) • Copiktra (duvelisib) • Ukoniq (umbralisib)
almost2years
G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy. (PubMed, Front Immunol)
Cell response to TG-1801 alone or combined with the U2 regimen associating ublituximab to the PI3Kδ inhibitor umbralisib, was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and/or quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). Genetic depletion and pharmacological inhibition of GPR183 impaired ADCP initiation, cytoskeleton remodeling and cell migration in 2D and 3D spheroid B-NHL co-cultures, and disrupted macrophage-mediated control of tumor growth in B-NHL CAM xenografts. Altogether, our results support a crucial role for GPR183 in the recognition and elimination of malignant B cells upon concomitant targeting of CD20, CD47 and PI3Kδ, and warrant further clinical evaluation of this triplet regimen in B-NHL.
Journal • Checkpoint inhibition • IO biomarker • Checkpoint block
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CD19 (CD19 Molecule) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • GPR183 (G Protein-Coupled Receptor 183) • SIRPA (Signal Regulatory Protein Alpha)
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Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • TG-1801
almost2years
Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=4, Completed, University of Colorado, Denver | Suspended --> Completed | N=24 --> 4 | Trial completion date: Dec 2023 --> Jun 2022
Trial completion • Enrollment change • Trial completion date
|
CD20 (Membrane Spanning 4-Domains A1)
|
Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
almost2years
Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma (clinicaltrials.gov)
P2, N=24, Suspended, University of Colorado, Denver | Trial primary completion date: Jul 2023 --> Jul 2022
Trial primary completion date
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CD20 (Membrane Spanning 4-Domains A1)
|
Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
almost2years
Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin's Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles. (PubMed, Molecules)
In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). The best interaction with gold was observed at the oxygen atom number 5 with -29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.
Journal
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PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
sirolimus • Ukoniq (umbralisib)
almost2years
PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise. (PubMed, Blood Lymphat Cancer)
Four selective PI3K inhibitors have received accelerated FDA approvals for the treatment of patients with relapsed/refractory (R/R) CLL and/or iNHL based mainly on single-arm Phase II studies: Idelalisib (PI3K-δ inhibitor), copanlisib (dual PI3K-α and PI3K-δ inhibitor), duvelisib (dual PI3K-γ and PI3K-δ inhibitor), and umbralisib (dual PI3Kδ and CK1ε inhibitor). Consequently, the class of PI3K inhibitors came under scrutiny, with an FDA expert panel voting on April 21, 2022, recommending that future FDA approvals of PI3K inhibitors be supported by randomized data, rather than single-arm data only, and further discontinuing the use of almost all the PI3K inhibitors in hematologic malignancies. As we believe further research is needed to help potentialize PI3K inhibitors by improving their safety profiles, this mini-review aims at revisiting the clinical successes, the failures, and the promising aspect of this class of drugs, while presenting possible ways that could benefit its successful development.
Review • Journal
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
Aliqopa (copanlisib) • Zydelig (idelalisib) • Copiktra (duvelisib) • Ukoniq (umbralisib)
almost2years
Enrollment open
|
CD4 (CD4 Molecule)
|
lenalidomide • doxorubicin hydrochloride • Gazyva (obinutuzumab) • cyclophosphamide • vincristine • Ukoniq (umbralisib) • Belrapzo (bendamustine RTD)
2years
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=12, Active, not recruiting, City of Hope Medical Center | Suspended --> Active, not recruiting | N=27 --> 12
Enrollment closed • Enrollment change • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
|
Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
|
Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
2years
Simultaneous Inhibition of PI3Kgamma and PI3Kdelta Deteriorates T-cell Function With Implications for Chronic Lymphocytic Leukemia. (PubMed, Hemasphere)
Here, we analyzed the impact of the clinically approved PI3Kδ inhibitors idelalisib and umbralisib, the PI3Kγ inhibitor eganelisib, and the dual-γ and -δ inhibitor duvelisib on the functional capacity of T cells. Extrapolation of this data to a clinical setting could provide an explanation for the observed irAEs in CLL patients undergoing treatment with PI3K inhibitors. Consequently, this highlights the need for a close monitoring of patients treated with PI3K inhibitors, and particularly duvelisib, due to their potentially increased risk of T-cell deficiencies and associated infections.
Journal • IO biomarker
|
PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
Zydelig (idelalisib) • Copiktra (duvelisib) • Ukoniq (umbralisib) • eganelisib (IPI-549)
2years
SWOG S1608: Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma (clinicaltrials.gov)
P2, N=95, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024
Trial completion date • Trial primary completion date
|
CD4 (CD4 Molecule)
|
lenalidomide • doxorubicin hydrochloride • Gazyva (obinutuzumab) • cyclophosphamide • vincristine • Ukoniq (umbralisib) • Belrapzo (bendamustine RTD)
2years
SWOG S1608: Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma (clinicaltrials.gov)
P2, N=95, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023
Trial completion date • Trial primary completion date
|
CD4 (CD4 Molecule)
|
lenalidomide • doxorubicin hydrochloride • Gazyva (obinutuzumab) • cyclophosphamide • vincristine • Ukoniq (umbralisib) • Belrapzo (bendamustine RTD)
over2years
Integrating High-Throughput Dynamic BH3 Profiling and Molecular Phenotyping to Identify Therapeutic Vulnerabilities in CLL (ASH 2022)
Despite recent advances in chronic lymphocytic leukemia (CLL) therapy, such as the use of targeted agents including, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the potent BCL-2 antagonist venetoclax, this disease remains incurable for most patients, who are refractory or become resistant to the novel agents...Other drugs that demonstrated high priming included navitoclax (BCL-XL/BCL-2), nutlin-3 (MDM2), abexinostat (HDAC), gandotinib (JAK2), duvelisib (PI3K δ/γ), idelalisib (PI3Kδ) and cerdulatinib (SYK/JAK)...First, we found that IGHV-mutated CLLs (M-CLLs) became more primed to apoptosis than IGHV-unmutated CLLs (U-CLLs) across the panel of drugs (p<0.001, paired t-test) and significantly in response to fludarabine and umbralisib (FDR<0.1, t-test)...EC-i, associated with the intermediate methylation subtype of CLL, was the most resistant EC to ibrutinib but was very sensitive to navitoclax, more than to any other drug. Altogether, we present a framework that links ex-vivo drug response with molecular features including expression subtypes to highlight new therapeutic opportunities in CLL.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • JAK2 (Janus kinase 2) • CD19 (CD19 Molecule) • IGH (Immunoglobulin Heavy Locus) • BCL2L1 (BCL2-like 1) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • CD5 (CD5 Molecule) • IL10 (Interleukin 10) • SYK (Spleen tyrosine kinase)
|
IGH mutation • IL10 overexpression • TS 12
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Zydelig (idelalisib) • Copiktra (duvelisib) • navitoclax (ABT 263) • Ukoniq (umbralisib) • fludarabine IV • abexinostat (CG-781) • cerdulatinib (ALXN2075) • Nutlin-3 • gandotinib (LY 2784544)
over2years
A Phase II Trial of Acalabrutinib in Combination with PI3Kδ Inhibitor Umbralisib and the Anti-CD20 Antibody Ublituximab (AU2) in Patients with Previously Untreated Mantle Cell Lymphoma (MCL) (ASH 2022)
Thus, AU2 is a highly effective regimen in patients with previously untreated MCL, including those with high-risk genetics (100% CR rate). While a combination of continuous umbralisib and acalabrutinib was associated with liver function test abnormalities, intermittent dosing of umbralisib was well tolerated.
Clinical • P2 data • Combination therapy
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TP53 (Tumor protein P53) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
|
Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over2years
Rapid Tumor Debulking of Relapsed/Refractory CLL Patients By PI3Kδ Inhibition and Anti-CD20 Monoclonal Antibody Treatment (ASH 2022)
The combination of a novel highly-specific phosphoinositide 3-kinase delta (PI3Kδ) inhibitor and casein kinase 1 epsilon (CSK1ε) inhibitor, umbralisib (UMB), and a glycoengineered chimeric monoclonal antibody (mAb) targeting a unique epitope on CD20, ublituximab (UBL), with the BCL2 inhibitor venetoclax (VEN) may decrease drug resistance, reduce risk of tumor lysis syndrome (TLS) and achieve higher levels of undetectable minimal residual disease (MRD). In conclusion, our initial data show that treatment with a selective PI3Kδ and CSK1ε inhibitor (UMB) combined with an anti-CD20 mAb (UBL) is effective in decreasing CLL cell counts in all patients assessed in the U2-VEN clinical trial. However, treatment efficacy could be limited by large decreases in the CLL surface CD20 levels.
Clinical
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CD19 (CD19 Molecule) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • CD5 (CD5 Molecule)
|
Venclexta (venetoclax) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over2years
Functional testing to characterize and stratify PI3K inhibitor responses in chronic lymphocytic leukemia. (PubMed, Clin Cancer Res)
Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CD19 (CD19 Molecule) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • CASP3 (Caspase 3)
|
Venclexta (venetoclax) • Aliqopa (copanlisib) • Zydelig (idelalisib) • Ukoniq (umbralisib)
over2years
CHOP U2: Clinical Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL) (clinicaltrials.gov)
P1/2, N=1, Terminated, University of Alabama at Birmingham | N=35 --> 1 | Trial completion date: Jun 2025 --> Jun 2022 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Jun 2022; FDA hold
Enrollment change • Trial completion date • Trial termination • Trial primary completion date
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • CD5 (CD5 Molecule)
|
Chr t(11;14)
|
doxorubicin hydrochloride • cyclophosphamide • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over2years
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=27, Suspended, City of Hope Medical Center | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023
Trial completion date • Trial primary completion date • Combination therapy
|
CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
|
Chr t(11;14) • CCND1 overexpression • Chr t(11;14)(q13;q32)
|
Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
over2years
Extended Abstract: New BTKi (SOHO 2022)
It has also been studied in combination with idelalisib or entospletinib in CLL and other B-cell lymphomas though without clear benefi t for the combinations over monotherapy16,17. Tirabrutinib is approved in Japan for WM, lymphoplasmacytic lymphoma (LPL), and RRPCNSL, and in South Korea for RR-PCNSL18. TG-1701 is a selective covalent BTKi that has been studied as a monotherapy and in combination with ublituximab and umbralisib with preliminary results suggesting both effi cacy and manageable safety19. Orelabrutinib, another selective covalent BTKi, has been studied as a monotherapy in CLL in addition to other B-cell malignancies, also with favorable safety and effi cacy20,21 and it is approved in China for rel/ref CLL and MCL22. Finally, DTRMWXHS-12 is a covalent BTKi that uniquely is being studied in combination with everolimus and pomalidomide (triplet referred to as DTRM-555), given that this combination was determined to lead to synthetic lethality in both in vivo and in vitro screening studies, with safety and activity seen in early studies23,24...This resistance mechanism appears shared among available irreversible BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib26...Three such inhibitors have completed phase 1 studies in CLL: vecabrutinib, nemtabrutinib, and pirtobrutinib with another currently in phase 1, luxeptinib...Subsequently, pirtobrutinib is being further studied as both a monotherapy and in combination with venetoclax-rituximab in phase 3 trials in both the frontline and relapsed/refractory settings in CLL in addition to MCL...These non-C481 BTK mutations conferred resistance across multiple non-covalent BTKi’s (in addition to pirtobrutinib, vecabrutinib, nemtabrutinib and fenebrutinib were tested) in addition to variable levels of resistance to covalent BTKi’s36...This is being accomplished by improved tolerability, allowing for patients to stay on drug for longer, and potentially improved effi cacy, including activity despite acquisition of C481 resistance mutations, in the case of the non-covalent inhibitors. The non-covalent inhibitors would help fi ll a major area of unmet need for CLL patients progressing on covalent BTK inhibitors who are not candidates for or progress following venetoclax therapy.
IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • PLCG2 (Phospholipase C Gamma 2) • IL2 (Interleukin 2) • ITK (IL2 Inducible T Cell Kinase)
|
Chr del(11q) • BTK C481S • PLCG2 mutation • BTK mutation • BTK C481
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib) • Zydelig (idelalisib) • Inokai (orelabrutinib) • entospletinib (GS-9973) • pomalidomide • Jaypirca (pirtobrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy) • edralbrutinib (TG-1701) • luxeptinib (CG-806) • vecabrutinib (SNS-062) • DTRM-555 • DTRMWXHS-12 • Velexbru (tirabrutinib) • fenebrutinib (RG7845) • nemtabrutinib (MK-1026)
over2years
Current status of phosphoinotiside-3 kinase inhibitors in blood cancers. (PubMed, Curr Opin Oncol)
With close monitoring and management of adverse events, PI3K inhibitors continue to have a role in therapy of R/R CLL and NHL. Strategies to mitigate adverse events and increase efficacy of PI3K inhibitors include time-limited combination approaches, intermittent dosing schedules.
Journal
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PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta)
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Aliqopa (copanlisib) • Zydelig (idelalisib) • Copiktra (duvelisib) • Ukoniq (umbralisib)
over2years
AU2 In Relapsed and Untreated CLL (clinicaltrials.gov)
P2; Recruiting --> Active, not recruiting
Enrollment closed
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clonoSEQ
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)
almost3years
Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma (clinicaltrials.gov)
P2, N=27, Suspended, City of Hope Medical Center | Recruiting --> Suspended | Trial primary completion date: Mar 2023 --> Sep 2022
Trial suspension • Trial primary completion date • Combination therapy
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CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1)
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CCND1 overexpression
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Calquence (acalabrutinib) • Ukoniq (umbralisib) • Briumvi (ublituximab-xiiy)