Background: Pre-clinical data suggest a role for SYK and JAK signaling pathways as oncogenic drivers in PTCL. Most compelling is the frequent demonstration of SYK expression (not expressed in normal T-cells) in PTCL and that transgenic expression of SYK in mouse T cells drives a lethal lymphoproliferative disorder. Frequent activating mutations to JAK/STAT pathways are also observed. Cerdulatinib is a small molecule reversible ATP competitive inhibitor of SYK and JAK1, JAK3 and TYK2. Methods: Eighteen relapsed/refractory PTCL patients were enrolled as part of a phase 2a study, receiving 30 mg cerdulatinib orally BID. Response was assessed by Lugano classification criteria at the end of 2 months and every 3 cycles thereafter. Results: Patients included PTCL-NOS (7), AITL (6), ALCL (2), HSTCL (1), Gamma-delta TCL (1), and EITL (1); median age 70 [48-84]; prior transplant 28%; and 44% refractory to last therapy. Eleven patients were evaluated for clinical response, 3 discontinued prior to evaluation (2 due to progression; 1 withdrew consent), and 4 patients have yet to be evaluated. Six patients have responded (ORR 43%). Of these, 4 achieved a CR after 2 cycles, 2 achieved a PR, and 2 SD. Four responding patients remain on drug: 1 for 11+ months and the remaining for 3-7 months. A patient with CR was referred to allogeneic transplant and censored after cycle 2. An additional patient achieved complete remission of target lesions, but discontinued therapy due to a new lesion. The majority of responses were observed in PTCL-NOS and AITL. Importantly, CRs and PRs occurred in patients who failed multiple lines of therapy, including pralatrexate, romidepsin, belinostat, and an investigational PI3K inhibitor. The most common AEs of any grade were diarrhea (33%), fatigue (22%), lipase increase (17%), and nausea (17%). Grade 3+ AEs occurring in ≥2 patients are neutropenia (4), diarrhea (3), lipase increase (2), and pneumonia (2). The target PK range was achieved with an average SSCmin of ~0.8 µM. Conclusions: These data suggest that cerdulatinib is well tolerated and capable of generating durable complete responses in heavily pre-treated PTCL. Clinical trial information: NCT01994382