A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (ONO/GS-4059) and Idelalisib with and without Obinutuzumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Introduction: Several targeted therapies have been added to the treatment landscape of CLL. These agents have more favorable toxicity profiles compared with chemotherapy, but achieve only low complete remission (CR) rates. However, combination regimens with targeted drugs have the potential for improved duration and depth of response while exhibiting an acceptable safety profile. Tirabrutinib is a selective, irreversible, second generation, small-molecule BTK inhibitor. Tirabrutinib and idelalisib individually have shown promising results as single-agent therapy in patients (pts) with CLL. This study evaluated tirabrutinib and idelalisib together as dual therapy (TI), and as triple therapy adding obinutuzumab (TIO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02968563) at 15 clinical centers in Germany that recruited between April 2017 and September 2018. Pts with relapsed or refractory CLL were eligible, including those who did not progress while treated with any inhibitor of BTK, SYK, PI3K, BCL-2, or with obinutuzumab. Pts received the TI regimen with tirabrutinib 80 mg once daily (QD) + idelalisib 100 mg QD, or TIO 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 TIO regimen. The primary endpoint was CR rate at week 25. Results: Thirty-five pts were enrolled, of which 5 were treated with TI and 30 with TIO. Median (range) age was 66 (47-82) years, with a median of 1 (1-1) and 1 (1-4) prior anticancer therapies in those assigned to TI and TIO, respectively. As of 7 June 2019, 1 of 5 pts (20%) on TI and 21 of 30 pts (70%) on TIO continue to receive tirabrutinib on study, while 1 pt (20%) in the TI and 19 pts (63%) in the TIO arm continued with idelalisib. Tirabrutinib dosing as specified per protocol at week 104 was completed by 1 pt (20%) in the TI and 4 pts (13%) in the TIO arm, respectively. No pts receiving TI and 4 pts (13%) on TIO completed idelalisib as specified per protocol. Altogether 3 pts out of 35 (9%) discontinued tirabrutinib and 7 pts (20%) discontinued idelalisib prematurely due to adverse events (AEs). Twenty-eight of 30 (93%) pts completed obinutuzumab dosing as specified per protocol. Four pts (80%) treated with TI and 29 pts (97%) treated with TIO were ongoing in the study. Median duration (range) of exposures to tirabrutinib and idelalisib were 67