cerdulatinib (ALXN2075) / Nicox, AstraZeneca - LARVOL DELTA

Management of Mycosis Fungoides and Sézary Syndrome With Oral Systemic Therapies. (PubMed, J Cutan Med Surg) - "FDA-approved oral therapies include bexarotene and vorinostat, both of which are effective in patients who are recalcitrant to prior topical therapies. Off-label oral therapies include methotrexate, acitretin, and chlorambucil...Chlorambucil is mainly used to treat erythrodermic MF. Investigational oral therapies for MF include tenalisib, duvelisib, cerdulatinib, lenalidomide, bortezomib, and azacytidine, and direct comparison studies between these investigational agents and FDA-approved therapies should be undertaken to better understand their role in the management of MF and SS."

Journal • Review • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

Results from an open-label phase 2a study of cerdulatinib, a dual spleen tyrosine kinase/janus kinase inhibitor, in relapsed/refractory peripheral T-cell lymphoma. (PubMed, Leuk Lymphoma) - P1/2 | "The most common grade ≥3 treatment-emergent adverse events were asymptomatic amylase elevation (23.1%), anemia (20.0%), and asymptomatic lipase elevation (18.5%). These data suggest clinical activity and acceptable tolerability for cerdulatinib in patients with relapsed/refractory PTCL."

Journal • P2a data • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • SYK

Identifying Novel Drug Vulnerabilities in Specified Molecular Subsets of Chronic Lymphocytic Leukemia (ASH 2024) - "Supporting the clinical and biological relevance of our results, venetoclax and ibrutinib were highly effective across CLL, nutlin-3 was ineffective in p53 mutant CLL. Novel drugs with the greatest pan-CLL effects include abexinostat, navitoclax, cerdulatinib, gandotinib and nutlin-3...We found many such associations including high sensitivity of IGHV-mutated CLL (M-CLL) to nutlin-3, IGHV-unmutated CLL (U-CLL) to Onalespib (MWU test, q<0.1), the intermediate epigenetic subtype (i-CLL) to Rapamycin (ANOVA, q<0.1). RNA subtype EC-m4 (TNF- and IFN- high M-CLLs) was specifically sensitive to nutlin-3 and onalespib; and EC-m2 (trisomy 12 enriched M-CLLs) demonstrated resistance to venetoclax and sensitivity to abexinostat (MWU test, p<0.05). Response to lenalidomide was associated with trisomy 12 (MWU, p=0.002)...In summary, we present an experimental strategy to rapidly prioritize novel treatments for CLL patients and a computational framework to inform precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD5 • IGH • TP53

Researchers at John Theurer Cancer Center, a member of the Georgetown Lombardi Comprehensive Cancer Center Consortium, participated in 46 studies presented at the 2019 American Society of Hematology’s Annual Meeting & Exposition (PRNewswire) - P2, N=105; ZUMA-2 (NCT02601313); Sponsor: Kite, A Gilead Company; P1, N=74; NCT03274219; Sponsor: bluebird bio; P3, N=200; ASCERTAIN (NCT03306264); Sponsor: Astex; "Experts at Hackensack Meridian Health John Theurer Cancer Center...participated in 46 studies presented over the last week at the American Society of Hematology's (ASH) 61st Annual Meeting & Exposition, held at the Orange County Convention Center in Orlando, FL from December 7-10."

P1 data • P2 data • P3 data • Cytomegalovirus Infection • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Mantle Cell Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

A Non-Canonical Role for the Glycosyltransferase Enzyme UGT2B17 as a Novel Constituent of the B Cell Receptor Signalosome. (PubMed, Cells) - "The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • SYK • UGT2B17 • ZAP70

The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B- and T-cell non-Hodgkin lymphoma (NHL). (ASCO 2018) - P1/2; "Durable PRs have occurred in patients who relapsed on BTK inhibitor (CLL, 5+ months, WM, 7+ months, FL, 12 months), venetoclax (SLL, 18+ months), and tenalisib (PTCL, 3+ months) therapy. The cerdulatinib phase 2 dose of 30 mg BID demonstrates good tolerability and efficacy in heavily pre-treated r/r B and T cell NHL."

Clinical • IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Indolent Lymphoma • Marginal Zone Lymphoma • Peripheral T-cell Lymphoma

[VIRTUAL] THE MYB-TYK2 GENE FUSION INDUCES B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA IN IN VITRO AND IN VIVO MODELS AND CAN BE EFFECTIVELY TARGETED BY THE DUAL SYK/JAK INHIBITOR, CERDULATINIB. (EHA 2020) - P1/2 | "Immunophenotypic analysis demonstrated arrest at pro/pre- B cell stage (CD45R/B220+, CD43­+, CD19+, CD24+, BP-1+ and IgM+/-)...In addition, cerdulatinib was identified as a novel drug against MYB-TYK2 altered disease in vitro and in vivo to aid development of targeted therapeutic approaches against this aggressive ALL subtype. This inhibitor may also be effective against other genomic alterations that result in aberrant JAK-STAT signalling."

Preclinical • Acute Lymphocytic Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD24 • CD43 • SYK

Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B Cell Malignancies: Results from a Phase I Dose Escalation Study (ASH 2017) - P1/2; "...Significant correlations were observed between inhibition of both SYK and JAK signaling pathways and tumor response, most notably the BCR and IL-4 signaling pathways...Importantly, 2 patients with ibrutinib-relapsed CLL who progressed within the first cycle of therapy with cerdulatinib had 3 mutations in common: p53, EP300, and BTK (C481S)...Moreover, the extent of target inhibition, as well as suppression of inflammation, correlated with tumor response. Cerdulatinib is currently under investigation as part of a phase IIa study to further evaluate efficacy and tolerability in this population."

Next-generation sequencing • P1 data • Biosimilar • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Immunology • Indolent Lymphoma • Mantle Cell Lymphoma

Efficacy and Safety of Topical JAK inhibitors in the Treatment of Atopic Dermatitis in Pediatrics and Adults: A Systematic Review. (PubMed, Exp Dermatol) - "Available topical JAKi are effective and safe modalities in treating AD. Nevertheless, further studies with longer duration and head-to-head comparative trials are necessary to find the best option with the least adverse effects."

Journal • Review • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pediatrics • Pruritus

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..."

IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CD19 • CD5 • IGH • IL10 • JAK2 • PIK3CD • SYK

Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy or in Combination with Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma (ASH 2021) - P1/2 | "The cerdulatinib + rituximab combination appeared to be well tolerated, with tumor reductions in all evaluable pts. These data provide proof of concept and a promising efficacy/safety profile for a first-in-class, dual SYK/JAK inhibitor in relapsed/refractory FL."

Clinical • Combination therapy • Monotherapy • P2a data • Cardiovascular • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Infectious Disease • Lymphoma • Neutropenia • Oncology • Pancreatitis • Pneumonia • Pulmonary Embolism • Respiratory Diseases • JAK1 • JAK2 • SYK • TYK2

Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (ASH 2021) - P1/2 | "Methods Eligible patients in the PTCL cohort were aged ≥18 years and had histologically confirmed PTCL with relapsed/refractory disease after ≥1 prior systemic therapy (prior brentuximab was required for CD30+ patients) and an Eastern Cooperative Oncology Group performance status ≤1. Overall the benefit/risk profile of cerdulatinib treatment appears favorable in this population, with the exception of the PTCL NOS subgroup, in whom no responses were seen. This subtype-specific activity raises the potential for biomarker identification to optimize patient selection."

Clinical • Monotherapy • P2a data • Anemia • Bone Marrow Transplantation • Follicular Lymphoma • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pancreatitis • Peripheral T-cell Lymphoma • Septic Shock • T Cell Non-Hodgkin Lymphoma • Transplantation • SYK • TNFRSF8

Phase 1/2A Dose Escalation Study in CLL, SLL or NHL (clinicaltrials.gov) - P1/2; N=220; Completed; Sponsor: Portola Pharmaceuticals; Active, not recruiting ➔ Completed

Clinical • Trial completion • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • CTCs

Tolerability and response of the novel SYK/JAK inhibitor cerdulatinib in a phase 2a study in relapsed/refractory peripheral t cell lymphoma (PTCL). (ASCO 2018) - P1/2; "Importantly, CRs and PRs occurred in patients who failed multiple lines of therapy, including pralatrexate, romidepsin, belinostat, and an investigational PI3K inhibitor. These data suggest that cerdulatinib is well tolerated and capable of generating durable complete responses in heavily pre-treated PTCL."

P2a data • Peripheral T-cell Lymphoma

THE NOVEL SYK/JAK INHIBITOR CERDULATINIB DEMONSTRATES GOOD TOLERABILITY AND CLINICAL RESPONSE IN A PHASE 2A STUDY IN RELAPSED/REFRACTORY PERIPHERAL T CELL LYMPHOMA (EHA 2018) - "Importantly, CRs and PRs occurred in patients who failed multiple lines of therapy, including pralatrexate, romidepsin, belinostat, and an investigational PI3K inhibitor. These data suggest that cerdulatinib is well tolerated and capable of generating durable complete responses in heavily pre-treated PTCL."

Clinical • P2a data • Chronic Lymphocytic Leukemia • Indolent Lymphoma • Peripheral T-cell Lymphoma

THE DUAL SYK/JAK INHIBITOR CERDULATINIB DEMONSTRATES RAPID TUMOR RESPONSES IN A PHASE 2A STUDY IN PATIENTS WITH RELAPSED/REFRACTORY B- AND T-CELL NON-HODGKIN LYMPHOMA (NHL) (EHA 2018) - P1/2; "SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition using entospletinib has demonstrated clinical activity in B cell malignancies. The cerdulatinib phase 2a dose of 30 mg BID demonstrated good tolerability and efficacy in patients with heavily pre-treated r/r B and T cell NHL."

Clinical • IO biomarker • P2a data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Indolent Lymphoma • Peripheral T-cell Lymphoma

THE DUAL SYK/JAK INHIBITOR CERDULATINIB DEMONSTRATES RAPID AND DURABLE TUMOR RESPONSES IN A PHASE 2 STUDY IN RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA - AS A SINGLE AGENT AND COMBINED WITH RITUXIMAB (EHA 2019) - "...Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting kinases involved in B-cell antigen receptor (BCR) signaling produces responses in ~50% of r/r patients; however, new agents with a more favorable therapeutic index over long-term administration are needed...The combination of cerdulatinib with rituximab appears to be well tolerated and led to tumor reductions in all patients evaluated. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL."

P2 data • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hypertension • Immunology • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Pain • Pancreatitis

The dual SYK/JAK inhibitor cerdulatinib demonstrates rapid tumor responses in a phase 2 study in patients with relapsed/refractory B- and T-cell non-Hodgkin lymphoma (NHL). (ASCO 2018) - P1/2; "Durable PRs have occurred in patients who relapsed on BTK inhibitor (CLL, 5+ months, WM, 7+ months, FL, 12 months), venetoclax (SLL, 18+ months), and tenalisib (PTCL, 3+ months) therapy. The cerdulatinib phase 2 dose of 30 mg BID demonstrates good tolerability and efficacy in heavily pre-treated r/r B and T cell NHL."

Clinical • IO biomarker • P2 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Indolent Lymphoma • Marginal Zone Lymphoma • Peripheral T-cell Lymphoma

Alexion Reports First Quarter 2021 Results (PRNewswire) - “ALXN2075…is a dual spleen tyrosine kinase and janus kinase (SYK/JAK) inhibitor being evaluated in a Phase 1/2a study in patients with relapsed/refractory chronic lymphocytic leukemia or B-cell or T-cell non-Hodgkin lymphoma. Data are expected in the second quarter of 2021.”

P1/2 data • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Expanded Access Program for Participants Who Completed Study 13-601 and Continue to Clinically Benefit From Cerdulatinib (clinicaltrials.gov) - P; N=N/A; Available; Sponsor: Alexion Pharmaceuticals

Clinical • New trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Cerdulatinib: Top-line data from P1/2a trial (NCT01994382) for lymphoma in H1 2021 (Alexion, 39th Annual J.P. Morgan Healthcare Conference (Virtual Meeting))

P1/2 data • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma

Cerdulatinib: Top-line data from P1/2a trial (NCT01994382) for lymphoma in H1 2021 (Alexion, 39th Annual J.P. Morgan Healthcare Conference (Virtual Meeting))

P1/2 data • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma

[VIRTUAL] Persistent Activation of JAK/STAT Signaling Plays an Important Role inin VitroJaki Resistance inTYK2-rearranged B-Cell Acute Lymphoblastic Leukaemia (ASH 2020) - "Consequently, the novel evidence of resistance mechanisms to JAKi, provide a rationale for the use of other small molecule inhibitors (e.g. HSP90i and HDACi), to potentially retain TYK2 degradation ability in resistant cells. This targeted approach may contribute to the treatment of patient withTYK2-rearranged ALL."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukaemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • JAK1 • JAK2 • JAK3 • STAT5 • SYK • TYK2

Phase 1/2A Dose Escalation Study in CLL, SLL or NHL (clinicaltrials.gov) - P1/2; N=220; Active, not recruiting; Sponsor: Portola Pharmaceuticals; Trial completion date: Jul 2020 ➔ Dec 2020; Trial primary completion date: Jul 2020 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Small Lymphocytic Lymphoma • T Cell Non-Hodgkin Lymphoma • BCL2 • CTCs

Follicular lymphoma: Complexities in combinations (OncLive) - "Bruce Cheson, MD: We’ve studied the SYK/JAK inhibitor, cerdulatinib, and we’ve treated a few patients and seen some responses, but it’s still way too early. We’re combining all of these agents....; Nathan Fowler, MD:...we’re seeing a reevaluation of these combination immunotherapy studies in B-cell malignancies, as well as in myeloma, until we can really figure out how to predict toxicity and reduce risk for patients....; Anas Younes, MD:...The best idea, and I think it’s not easy, is to step back and perform these synergy analyses in independent laboratories and then prioritize which ones have the highest chance of being beneficial or synergistic...."

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