Background: Cerdulatinib is a selective, potent inhibitor of SYK, JAK1, JAK3, and TYK2. Preclinical and clinical data suggest that combined SYK/JAK inhibition may have activity in B- and T-cell NHL. SYK is a key regulator of BCR signalling (upstream of BTK and PI3K), and is also expressed in T-cell lymphomas. Preclinical studies suggest it may be an oncogenic driver in PTCL. Frequent activating JAK/STAT mutations are observed in B and T cell NHL. A phase 1 dose escalation study of cerdulatinib in 43 patients with r/r CLL and NHL was completed in 2016. Complete inhibition of SYK and JAK was well tolerated and consistent antitumor activity was seen in CLL and FL. Methods: This phase 2a study intended to confirm the safety and efficacy of cerdulatinib dosed 30 mg orally BID in patients with r/r B- and T-cell lymphoma. Dose reductions were permitted to a minimum of 15mg BID. Response was assessed by Lugano Classification criteria. Results: 99 patients enrolled (FL: 36, CLL/SLL: 28, PTCL: 18, marginal zone lymphoma: 8, aggressive: 5, Waldenstrom’s macroglobulinemia: 4). Median age is 68 (42-93) and median # of prior therapies is 3 (1–13). 30 patients had prior BTK, PI3K or BCL-2 inhibitor therapy. The most common AEs of any grade are diarrhea (42%), fatigue (36%), and nausea (32%). Grade 3+ AEs occurring in ≥5% patients are neutropenia (18%), lipase increase (15%), pneumonia (12%), diarrhea (10%), and fatigue (7%). 5 patients have had Grade 5 infections considered related to study drug (3 of 5 in the CLL cohort). The target PK range has been achieved with an average SSCmin of ~0.8 µM. Broad activity seen: 61% ORR in CLL/SLL, 50% in FL, and 43% in PTCL (4 CRs, 2 PRs in 14 patients). The first PTCL patient achieved a CR and is on drug at 11 months. Responses typically occurred after 2 cycles of treatment. 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. Updated PK/PD, safety and efficacy will be presented. Conclusions: 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 trial information: NCT01994382