200 mg pembro) and 7 with RT (4 at 100 mg pembro / 3 at 200 mg). Demographics: M/F (12/6), med age 69.5 yrs (range 53-81), med prior tx 2 (1-9) (for RT, med prior was 5, all ibrutinib refractory), 83% refractory to immediate prior tx. 13/14 BTK exposed pts were refractory. 61% were high risk (del17p, del11q, TP53 mut, Notch1 mut or complex karyotype). AE’s (all causality) were manageable. Grade 3/4 AE’s included neutropenia (n=6, 33%), ALT/AST increase (n=3, 17%), and thrombocytopenia (n=3, 17%). One DLT occurred at 200 mg dose level (ALT/AST elevation). MTD not reached. No increase in expected Gr≥ 3 PI3Kδ-associated toxicities noted (1 pneumonitis, no colitis events). ORR was 91% for CLL pts, with 7/11 pts progression free at median f/u of 24.8 mos, including one CLL pt off all therapy for 32+ mos. ORR was 83% in BTK refractory pts (5/6); notably 80% of BTK refractory CLL pts achieved a response to Umbra + UTX (U2) induction alone prior to the addition of pembro. 5/7 RT pts were available for efficacy (1 ineligible, 1 too early to evaluate): 2 CR, 1 SD (40%#) and 2 PD. RT CRs were durable (20+ mos and 12 mos, each); both were ibrutinib refractory, had 7 (including SCT) and 8 prior lines respectively, and one had failed CAR-T. Fig 1 is a Swimmer Plot of time on study. Correlative studies demonstrated relative retention of Tregs. Conclusion: The triple combination of umbralisib + ublituximab + pembrolizumab was well-tolerated. Responses were durable in BTK refractory, high risk pts, including two CRs in RT pts. Data suggests that time-limited therapy could be possible. Enrollment is ongoing in both the CLL and RT cohorts and an amendment is planned to evaluate the triplet combination of U2 + TG-1501 (PD-L1 mAb).