Syk Inhibitor Entospletinib In Combination With Obinutuzumab Demonstrates Efficacy In Patients With Relapsed/ Refractory Chronic Lymphocytic Leukemia (Cll)

B-cell receptor (BCR) signaling kinases are important targets in therapy of CLL. Resistance of lymphoid niche-resident CLL cells to BCR-signaling inhibition is fostered by the tumor microenvironment. We found that stromal B-cell activation factor (BAFF)-mediated activation of spleen tyrosine kinase (SYK) triggered BCR signaling, thereby contributing to apoptosis resistance in CLL cells (Paiva et al, 2017). The SYK inhibitor entospletinib (ENTO) abrogated BAFF-mediated BCR signaling accompanied by a decrease in pSTAT3 and MCL1 in vitro. We designed a Phase I/II investigator-sponsored trial of ENTO in combination with Obinutuzumab (Obin) in patients (pts) with relapsed/refractory CLL and non-Hodgkin lymphoma (NHL). Eligible pts were aged ≥18 years, had CLL/NHL (Phase I) or CLL (Phase II), relapsed and/or refractory to ≥1 prior therapies (no prior SYK inhibitor), ECOG performance status ≤2 and preserved organ function. The Phase I part of the study followed a standard 3+3 design with two dose levels (DL1: ENTO 200 mg PO BID; DL2 - ENTO 400 mg PO BID). ENTO was given for 7 days (run-in). Subsequently, Obin was given IV concurrently with ENTO on days 1, 2, 8, 15 of Cycle 1 and Day 1 of Cycles 2-6 in standard doses. ENTO was given until disease progression. Primary study objectives were toxicity (Phase I) and efficacy (objective response rate (ORR); Phase II). Correlative analysis of samples was performed at baseline, after run-in phase (7 days of entospletinib single agent) and after 6 cycles of combination therapy. Reverse protein phase array was performed at the RPPA core facility at MD Anderson Cancer Center. T cell populations and cytokine production were analyzed by flow cytometry.