Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). A published study described a unique translocation in 17% of PTCL specimens resulting in a SYK-ITK fusion protein, in which the kinase domain of SYK was constitutively active. This fusion protein was expressed transgenically in T cells in mice, resulting in a lethal T-cell proliferative disease, while its expression in B cells did not result in clonal expansion. Expression of wildtype SYK in PTCL is frequently observed. Additionally, gene expression profiling implicates JAK/STAT signaling in this disease and frequent activating mutations to common γ chain, JAK1, JAK3, or STAT5b are observed.
SYK expression is also reported in Mycosis Fungoides (MF), the most common variant of CTCL. Moreover, malignant T cell clones from CTCL patients secrete a host of Th2 cytokines (IL3, IL4, IL5, IL6, IL10, and IL13) and exhibit deregulation of the IL2 receptor signaling pathway. These cytokines mostly signal via JAK/STAT and promote T-cell proliferation and survival, and are potential mediators of pruritus. Overall, the data suggest that dual inhibition of SYK and JAK may perturb multiple and independent survival mechanisms in PTCL and CTCL.
Cerdulatinib is a small-molecule reversible ATP competitive inhibitor of SYK and JAK family members. In a phase 1 study in patients (pts) with B-cell malignancies, the recommended phase 2 dose was identified with a favorable safety profile and initial evidence of clinical activity. Subsequently, disease-specific phase 2a expansion cohorts were opened. The results of expansion cohorts in PTCL and CTCL are reported below.
Methods: Pts with relapsed/refractory PTCL or CTCL who had 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 pts accrued and if ≥3 responses were observed the cohort expanded to 40 pts. Both PTCL and CTCL cohorts have completed the first stage. The primary endpoint is response according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Pts are treated until progression, intolerance, or response adequate to allow stem cell transplantation (SCT). All pts receive antimicrobial prophylaxis (typically Bactrim).
Results: As of July 26, 38 pts with PTCL and 22 with CTCL have received cerdulatinib. Pt characteristics: median (range) age: PTCL: 65 (34-84) years and CTCL: 63 (24-39) years; median prior systemic therapies: PTCL: 3 (1-10) and CTCL: 3 (1-12); 21% of PTCL pts and 5% of CTCL pts had prior SCT; refractory to last therapy: PTCL: 53% and CTCL: 50%. In the PTCL cohort: 26 pts are evaluable for response and 12 pts have yet to reach their first assessment. The ORR is 35% (9/26) and CR is 31% (8/26). Seven responding pts remain on drug for 3-12+ months, 1 proceeded to allogeneic SCT after achieving a CR, and 1 progressed at 15 months. Responses have been observed in pts with AITL, PTCL-NOS, and gamma-delta TCL. In the CTCL cohort: 10 pts are evaluable for response and 12 have yet to be evaluated. The ORR is 50% (5/10) and CR is 10% (1/10). All responders and 2 pts with stable disease remain on drug. Responses have been seen in pts with MF and Sezary Syndrome. Rapid improvements in pruritus appear to correlate with clinical response.
Among all pts, the most common AEs of any grade were diarrhea (30%), lipase increase (20%), amylase increase (18%), nausea (13%), and neutropenia (12%). AEs ≥ Grade 3 occurring in ≥3 pts were lipase increase (n=9), neutropenia (n=6), and amylase increase (n=6). The amylase and lipase increases occurred without clinical pancreatitis and resolved with dose reduction or dose interruption.
Conclusion: In ongoing 2 stage expansion cohorts, cerdulatinib has shown good tolerability and sufficient activity in both PTCL and CTCL to proceed to the second stage. Significant efficacy includes both complete and durable responses across a spectrum of PTCL and CTCL subtypes. Correlative studies are aimed at identifying predictors of response. This phase 2a study will inform the design of a pivotal trial in T-cell lymphoma.
Horwitz:Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Feldman:Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Khodadoust:Innate Pharma: Research Funding. Kim:Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Soligenix: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; miRagen: Research Funding. Munoz:Gilead: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Juno: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Alexion: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy. Phillips:Genentech: Consultancy; Gilead: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Genentech: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. Wilcox:Incyte, Corp: Research Funding. Steele:Portola Pharmaceuticals, Inc.: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment. Birrell:Portola Pharmaceuticals, Inc.: Employment. Leeds:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola: Employment. Michelson:Portola Pharmaceuticals, Inc.: Employment. Coffey:Portola Pharmaceuticals, Inc.: Employment. Curnutte:Portola Pharmaceuticals, Inc.: Employment. Hamlin:Portola: Consultancy.
Asterisk with author names denotes non-ASH members.