Background: SYK and JAK signaling pathways may be critical mediators in the pathogenesis of peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). SYK expression is observed in these malignant cells, and pre-clinical data suggest it acts as an oncogenic driver possibly by mediating chronic T-cell antigen receptor-independent signaling. Consistently, transgenic expression of constitutively active SYK in CD4+ T cells in mice results in a lethal T-cell proliferative disease, while its expression in B cells did not result in clonal expansion. Moreover, evidence for JAK/STAT pathway involvement in these diseases has been demonstrated by gene expression profiling, and frequent activating mutations to common γ chain, JAK1, JAK3, or STAT5b are observed in PTCL. Malignant T-cell clones from CTCL patients secrete a host of Th2 cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13) and exhibit deregulation of the IL-2 receptor signaling pathway. These cytokines induce JAK/STAT signaling, which may promote T-cell proliferation and survival. Overall, the data suggest that dual inhibition of SYK and JAK may perturb multiple and independent survival mechanisms implicated in PTCL and CTCL.
Cerdulatinib is a small-molecule reversible ATP competitive inhibitor of SYK and JAK family members. Results of cerdulatinib single-agent 30 mg BID in a phase 2a dose expansion study in patients with PTCL and CTCL are reported here.
Methods: Patients with relapsed/refractory PTCL or CTCL who received at least 1 prior systemic therapy were eligible to be treated with cerdulatinib at 30 mg orally BID. These expansion cohorts were enrolled in 2 stages: initially 20 patients accrued and, if ≥3 responses were observed, the cohort was expanded. The primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Patients are treated until progression, intolerance, or response adequate to allow stem cell transplantation. All patients receive antimicrobial prophylaxis (typically sulfamethoxazole and trimethoprim [Bactrim]).
Results: An interim analysis of 61 patients with PTCL and 37 with CTCL who received cerdulatinib as a single agent was performed on July 18, 2019. Patient characteristics: median (range) age: PTCL: 65 (21-85) years and CTCL: 62 (24-80) years; median prior systemic therapies: PTCL: 2 (1-12) and CTCL: 5 (1-16); refractory to last therapy: PTCL: 48% and CTCL: 62%. For PTCL and CTCL combined, 41% of patients received prior romidepsin, 5% received prior belinostat, 12% received prior pralatrexate, and 32% received prior brentuximab.
In the PTCL cohort, 60 patients were evaluable for response (overall response rate [ORR] of 35%). Responses were primarily seen in AITL/TFH subtype (ORR of 55% [12 of 22], of which 41% of patients achieved a complete response [CR]). Responses have additionally been observed in patients with PTCL-NOS, ATLL, ALCL, and gamma-delta TCL. The ORR in CTCL patients was 35%, with the greatest activity observed in mycosis fungoides (ORR of 45%, of which 9% of patients achieved CR) versus Sezary syndrome (ORR of 17%, with no CR). Rapid improvements in pruritus have been observed in CTCL patients, independent of tumor response. Median duration of response is pending for both cohorts, but several patients have been in response for over a year.
Among all patients, the most common (>5% incidence) treatment-emergent grade 3+ adverse events were lipase increase (21%) and amylase increase (18%), diarrhea (8%), neutropenia (8%), anemia (7%), and fatigue (6%). Grade 3+ infections occurred in 29% of patients, which were generally managed by standard care. The amylase and lipase increases occurred without clinical pancreatitis and resolved irrespective of dose modification.
Conclusion: Cerdulatinib has shown good tolerability and clinical activity in PTCL and CTCL. Complete and durable responses across a spectrum of PTCL and CTCL subtypes were observed. Correlative studies are aimed at identifying predictors of response and resistance. This phase 2a study will inform the design of a pivotal trial in T-cell lymphoma.
Horwitz:Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; ADCT Therapeutics: Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Aileron: Research Funding; Aileron: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Trillium: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Portola: Consultancy; Affimed: Consultancy. Feldman:Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Portola Pharma: Research Funding; Pfizer: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Khodadoust:Corvus Pharmaceuticals: Research Funding. Kim:Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Elorac: Research Funding; Merck: Research Funding; Galderma: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; miRagen: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Soligenix: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Trillium: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Fosunkite: Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Patel:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Phillips:Celgene: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Smith:Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Smith:Portola Pharmaceuticals: Research Funding. Wilcox:Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; CTI Biopharma: Research Funding; Incyte: Research Funding. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.
Author notes
Asterisk with author names denotes non-ASH members.
