A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Entospletinib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Kutsch Nadine , Pallasch Christian , Tausch Eugen , Boehme Volkmar , Ritgen Matthias , Liersch Ruediger , Wacker Alexander , Jacobs Georg , Trappe Ralf Ulrich , Dreger Peter , Stilgenbauer Stephan , Zhang Danjie , Jürgensmeier Juliane M. , Bhargava Pankaj , Hallek Michael , Eichhorst Barbara F. 
Published: November 2019

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.