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Introduction: In CLL, numerous new therapeutic options have been introduced recently, without establishing a definitive standard therapy or cure for most patients (pts). An advantage of targeted therapies is the avoidance of toxicities associated with chemotherapy. However, all new kinase inhibitors used for treatment of CLL have low rates of complete remission (CR). Combinations of targeted agents have the potential to improve outcomes, shorten treatment duration, and reduce toxicity. Tirabrutinib (a BTK inhibitor), and entospletinib (a SYK inhibitor), both show significant single-agent clinical activity in pts with CLL. In this study, we evaluated tirabrutinib and entospletinib as dual therapy (TE), and as triple therapy in combination with obinutuzumab (TEO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02983617) at 15 clinical centers in Germany that recruited pts with relapsed or refractory CLL between April 2017 and September 2018. As of amendment 3, pts who did not progress while on an inhibitor of BTK, SYK, PI3K, BCL-2 or on obinutuzumab were also included. Pts received the TE regimen with tirabrutinib 80 mg once daily (QD) + entospletinib 400 mg QD for up to 104 weeks, or the TEO regimen adding obinutuzumab at standard dosing for a total of 8 doses of 1000 mg over 21 weeks. After the implementation of protocol amendment 3, randomization was discontinued and all subsequently enrolled pts received the TEO regimen. Response was measured by modified iwCLL 2008 criteria. The primary endpoint was the CR rate at week 25. Results: Thirty-six pts were treated, 6 with TE and 30 with TEO. Median (range) age was 68 (45-82) years, with a median of 1 (1-2) and 2 (1-8) prior anticancer therapies in those assigned to TE and TEO, respectively. As of 16 May 2019, 29 of all 36 pts (81%) continue to receive tirabrutinib and entospletinib on study; 2 (6%) pts completed study drug dosing as specified per protocol at week 104. Twenty-eight of 30 pts (93%) in the TEO arm completed obinutuzumab dosing as specified per protocol. Of the 36 pts, 34 (94%) continued the study and 2 (6%) discontinued the study due to adverse events (AEs) or death, both were in the TEO group. Median duration (range) of exposure to tirabrutinib and entospletinib was 99 (90-105) weeks on TE and 50 (4-104) weeks on TEO, including 20 (2-35) weeks for obinutuzumab. At week 25, CR rate was 0% (90% confidence interval [CI] 0-39.3) with TE and 7% (90% CI 1.2-19.5) with TEO (Table 1). Overall response rates at week 25 were 100% (90% CI 60.7-100) and 90% (90% CI 76.1-97.2) for TE and TEO.One pt on the TEO regimen experienced disease progression (per clinical response assessment) after 3.75 months of therapy. Three (10%) pts on TEO were minimal residual disease (MRD) negative in peripheral blood (PB MRD-) at week 25; one (3%) pt was also MRD negative in bone marrow (BM MRD-).No pts showed MRD negativity with TE therapy. Best rate of CR/PB MRD- was 7% (90% CI 1.2-19.5) and for CR/BM MRD- was 3% (90% CI 0.2-14.9) with TEO. Median time to first PB MRD- was 32 weeks on TEO. Median progression-free survival (PFS) and overall survival have not been reached yet, and 24-month PFS rates were not yet estimable in either treatment group. Treatment-emergent AEs (TEAEs) are listed in Table 2. No pt in the TE and 3 pts (10%) in the TEO group discontinued tirabrutinib and entospletinib due to TEAEs, and no pt discontinued obinutuzumab due to TEAEs. Two (7%) pts in the TEO arm died following a TEAE: an 82-year-old male from subdural hematoma (onset within 30 days of last dosing, and death within 68 days) and a 77-year-old male from syncope (onset on the last dosing date, and death at day 35 after last dosing); both deaths were considered unrelated to study treatment by investigators. Conclusion: A triple combination with tirabrutinib, entospletinib, and obinutuzumab (TEO regimen) was tolerable and demonstrated excellent therapeutic activity in pts with relapsed or refractory CLL, but with limited CR rate. Disclosures Kutsch: Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Pallasch:Gilead Sciences, Inc.: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Boehme:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Glenmark Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Helsinn: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; VioPharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; InCyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Wacker:Celgene: Consultancy; Roche: Consultancy; BMS: Consultancy; Incyte: Consultancy; Amgen: Consultancy. Trappe:Celgene, Janssen, Takeda, TEVA: Other: Congress related travel support ; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharma: Consultancy, Honoraria, Other: Congress related travel support , Research Funding; AbbVie: Consultancy, Other: Congress related travel support . Dreger:AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhang:Gilead Sciences, Inc.: Employment, Other: Shareholder. Jürgensmeier:Gilead Sciences, Inc.: Employment, Other: Shareholder. Bhargava:Gilead Sciences, Inc.: Employment, Other: Shareholder; Tioma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dicerna Pharmaceuticals: Consultancy; Sanofi, Aveo Pharma: Patents & Royalties. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Introduction: Entospletinib is an orally bioavailable, selective inhibitor of spleen tyrosine kinase. Targeting the B-cell receptor (BCR) signaling pathway with Bruton's tyrosine kinase (BTK) and PI3Kd inhibitors (BTKi and PI3Kdi), approved for treatment of chronic lymphocytic leukemia (CLL), has been a successful therapeutic strategy. Entospletinib is active in CLL and preclinical data suggest that entospletinib may be effective even in the context of resistance to BTKi, including that conferred by activation of PLCγ2 (Liu et. al. Blood 2015). Methods: This is an ongoing phase 2 trial (NCT01799889) of entospletinib in CLL and non-Hodgkin lymphoma. The study protocol includes 2 CLL cohorts for patients who have been previously treated with BTKi or PI3Kdi and 2 additional cohorts for patients with Richter's transformation who have had analogous prior treatment. Patients were treated with entospletinib monotherapy (400 mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2 to 3 months as previously described (Sharman et. al. Blood 2014). Results: As of June 28, 2016, 34 patients have been enrolled, and 33 have been treated. Of the 28 patients without Richter's transformation, 23 were previously treated with a BTKi (22 ibrutinib, 1 CC-292) and 5 with a PI3Kdi (idelalisib). Median number of prior treatments was 3 (1-7) for patients with prior BTKi and 5 (3-8) for prior PI3Kdi treatment. In total, 35% of the BTKi patients and 60% of the PI3Kdi patients had either a TP53 mutation or del17p; 75% did not have IgHV hypermutation. A median of 2 months (0-14) had elapsed since the prior treatment; 17 patients had progressive disease on prior therapy, while 11 discontinued prior therapy due to intolerance. Thirteen of the 28 patients enrolled without Richter's transformation remain on study with a median PFS of 5.6 months for the prior BTKi cohort and a median PFS of 6.9 months for the prior PI3Kdi cohort. Of the 15 patients who have stopped therapy, 9 discontinued due to disease progression, 5 discontinued due to an AE, and 1 withdrew consent. Overall, 19 patients were evaluable for response (15 BTKi/4 PI3Kdi; Table 1). Of the 6 patients who achieved a PR, all lacked IgHV hypermutation and 3 had either a TP53 mutation or del17p, and 3 had progressed on prior therapy. Following Richter's transformation, 5 patients have been treated with entospletinib (3 with prior BTKi therapy and 2 with prior PI3Ki). The interval since prior treatment was short ( All patients on study experienced a treatment-emergent AE (TEAE) and 49% experienced a serious AE (SAE; Table 2). Only 1 SAE, pancreatitis, was attributed to entospletinib. The most common TEAEs and laboratory abnormalities are listed in Table 2. Additional Grade ≥3 TEAEs reported in more than 1 patient included sepsis (3), atrial fibrillation (2), dehydration (2), neutropenia (2), pneumonia (2), respiratory failure (2), and urinary tract infection (2). The only TEAE attributable to entospletinib that led to discontinuation of treatment was fatigue. Five patients died on study; 2 from progressive disease and 1 each from heart failure, Guillain-Barre syndrome, and cardiac arrest; 3 of these 5 patients died within 30 days of the last dose of study drug [disease progression (2), cardiac arrest (1)]. Conclusion: Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Kdi. Continued investigation of treatment with entospletinib following progression after therapy with BCR signaling pathway inhibitors is warranted. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Shustov:Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Seattle Genetics: Research Funding; Novartis: Research Funding; BMS: Consultancy, Honoraria. Smith:Celgene: Honoraria; Spectrum: Honoraria; Abbvie: Research Funding; Genentech: Honoraria. Kolibaba:Cell Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Abella-Dominicis:Gilead Sciences: Employment, Equity Ownership. Zhang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Seattle Genetics: Research Funding. Awan:Pharmacyclics: Consultancy; Innate Pharma: Research Funding; Novartis Oncology: Consultancy.

Introduction: Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR)-signaling pathway has been the focus in many types of B-cell related hematological malignancies including mantle cell lymphoma (MCL). Methods: This reports the MCL cohort in a phase 2 trial that more broadly evaluated the efficacy and safety of entospletinib (800 mg BID) in patients with relapsed and refractory hematological malignancies (NCT01799889). Tumor response was assessed per Cheson 2007 criteria with imaging planned at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 16. All efficacy data were assessed by an Independent Review Committee. Results: A cohort of 39 patients with MCL was enrolled. The median age was 72 years (range: 49-92), 64% were male, and a median number of prior regimens were 2 (range: 1-6). Prior therapy included anti-CD20 antibodies (95%), alkylating agents (95%; bendamustine 44%), and anthracyclines (77%). Three patients (8%) have received ibrutinib either as investigational drug (n = 1) or as an approved drug (n = 2), and 1 patient (3%) received idelalisib. Median duration of treatment was 21 weeks (range: 1-87), with 1 patient continuing on treatment. Thirty-five (90%) patients were evaluable for tumor response. Four patients (10%) discontinued prior to initial tumor assessment: death (n = 1), disease progression (n = 2) and investigator's discretion (n = 1). The most common TEAEs (any grade/≥gr 3, independent of causality) and common lab abnormalities are summarized in Table 1. There were 4 TEAEs that led to study drug discontinuation (all n = 1): cardiac arrest, pruritus, pyrexia, and maculopapular rash. Six deaths were reported, none of which were related to study drug. The ORR was 15% (90% CI: 6.9%, 28.1%), with 6 (15%) patients achieving a PR and 23 (59%) patients maintaining a stable disease. The PFS rate at week 16 was 66% (95% CI: 46%, 79%). Median PFS was 5.6 months (95% CI: 3.6 months, 8.9 months). These results are based on data analysis of June 28, 2016. Conclusion: Entospletinib was well tolerated and demonstrated modest activity in patients with relapsed or refractory MCL. Further development of entospletinib in MCL will focus on the development of combination therapy. Figure 1 Waterfall Plot of Best % Change from Baseline in SPD. Figure 1. Waterfall Plot of Best % Change from Baseline in SPD. Figure 2 Kaplan-Meier Curve of Progression-Free Survival. Figure 2. Kaplan-Meier Curve of Progression-Free Survival. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Kolibaba:Amgen: Research Funding; Celgene: Research Funding; Cell Therapeutics: Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Novartis: Research Funding. Nay:Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria, Other: Advisory board; Celgene: Honoraria, Other: Advisory board; Amgen: Other: Advisory board; Lyndbeck: Honoraria; BMS: Honoraria. Zhang:Gilead Sciences: Employment, Equity Ownership. Shi:Gilead Sciences, Inc.: Employment, Equity Ownership. Forero:University of Alabama at Birmingham: Research Funding. Assouline:BMS: Speakers Bureau; Lundbeck: Consultancy; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau.