PHASE I/II STUDY OF UMBRALISIB (TGR‐1202) IN COMBINATION WITH UBLITUXIMAB (TG‐1101) AND PEMBROLIZUMAB IN PATIENTS WITH REL/REF CLL AND RICHTER'S TRANSFORMATION

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Introduction: Preclinical data suggest that PD-1 mediates immune evasion in CLL, however clinical data indicate that pembrolizumab (pembro) monotherapy is ineffective in r/r CLL patients (pts) (0% ORR; Ding, BLOOD 2017). We hypothesized synergistic activity with PD-1 + PI3K blockade. Umbralisib (Umbra), is a PI3Kδ inhibitor with unique effect on CK1ε. We conducted a Ph 1 (3+3 design) study to assess the safety and activity of Umbra with the anti-CD20 mAb ublituximab (UTX) and pembro in r/r CLL and RT - the first reported triple combination of a PD-1 inhibitor + PI3Kδi + anti-CD20 mAb. Methods: Treatment for CLL: Induction: Umbra (800mg daily) + UTX (900mg 3 out of 4 wks) for two 28-day cycles (Cy). Consolidation (Cy3-6): Pembro (dose level 1=100mg, dose level 2=200mg) every 3 wks + Umbra 800mg daily + UTX (900mg in Cy4 & 6). Maintenance: Cy≥6, Umbra 800 mg daily. For RT pts, all study drugs started in Cy1: Umbra 800 mg daily + UTX 900 mg Cy1 (D1, 8, 15), D1 Cy2-4, Cy7 and q3 cycles thereafter + pembro D3 of Cy1 and D2 of Cy2-4. Primary endpoint safety; secondary efficacy. Peripheral blood and/or BM was obtained for correlates at screening, Cy2, & Cy6. Results: 18 pts treated to date: 11 CLL (5 at 100 mg pembro / 6 at 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. Keywords: chronic lymphocytic leukemia (CLL); Richter's syndrome (RS). Disclosures: Mato, A: Consultant Advisory Role: TG Therapeutics, Inc., Genentech, PCYC, Loxo, Abbvie, Sunesis, Celgene, Verastem; Research Funding: TG Therapeutics, Inc., PCYC, Loxo, Abbvie, Regeneron, Sunesis. Dorsey, C: Consultant Advisory Role: TG Therapeutics, Inc. Brander, D: Consultant Advisory Role: TG Therapeutics, Inc. Purdom, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Paskalis, D: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Sportelli, P: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Miskin, H: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Weiss, M: Employment Leadership Position: TG Therapeutics, Inc.; Stock Ownership: TG Therapeutics, Inc. Shadman, M: Consultant Advisory Role: Abbvie, Genentech, Sound Biologics; Verastem, ADC therapeutics, Atara Biotherapeutics; Research Funding: Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck.

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