A phase I/II study of the SYK inhibitor entospletinib in combination with obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)

Background: B‐cell receptor (BCR) signaling kinases are important targets in therapy of CLL. However, incomplete responses and emerging resistance to targeted agents justifies development of novel combination strategies. Resistance of lymphoid niche‐resident CLL cells to BCR‐signaling inhibition is, in part, fostered by the soluble mediators present in the tumor microenvironment. Among these, B‐cell activating factor (BAFF) is critical in the survival of both healthy and neoplastic B‐cells. We found that BAFF‐mediated activation of spleen tyrosine kinase (SYK) triggered BCR signaling, thereby contributing to apoptosis resistance in CLL cells. The SYK inhibitor entospletinib (ENTO) abrogated BAFF‐mediated BCR signaling and down‐modulated the anti‐apoptotic protein MCL1 in vitro. Moreover, an anti‐CD20 antibody, obinutuzumab (Obin), downregulates BCLX in neoplastic B‐cells. Aims: Armed with this mechanistic knowledge, we designed a Phase I/II investigator‐sponsored trial of ENTO in combination with Obin in patients (pts) with relapsed/refractory (R/R) CLL and non‐Hodgkin lymphoma (NHL). Methods: 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). Obin was given IV 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). Results: At DL1 of Phase I, six pts were enrolled (4 ‐ CLL; 2 ‐ follicular lymphoma). One pt experienced a dose‐limiting toxicity (DLT: grade 3 asymptomatic LFT abnormalities which failed to resolve within 72 hours) attributed to ENTO. Other grade 3–4 toxicities included 2 grade 3 infusion reactions and one transient grade 4 neutropenia (attributed to Obin). Four pts remain on therapy after a median follow‐up of 15 months. Three pts were enrolled at DL2 without DLTs. In Phase 2, 18 pts with CLL received ENTO 400 mg PO BID (in combination with Obin). One pt was deemed ineligible due to Richter's transformation at study entry. Of the 17 evaluable pts, 71% were men. Median age was 66 years (range 47–76), and 76% were aged >65 years. 94% had ECOG performance status ≤1. Four pts (24%) had a complex karyotype, 2 (12%) had del(17p) and 8 (48%) had del(13q). Median number of prior therapies was 2 (range, 1–6): 47% had received prior fludarabine and 53% bendamustine. 29% received prior ibrutinib. As of February 1, 2019, with median follow‐up of 8 months (range, 6–14 months), 83% of pts (14/17) remain on treatment. Median relative dose intensity of ENTO (ratio of actual to planned cumulative dose during drug exposure period) was 80%. ORR was 76% (95% CI: 50–93%): 12 (70%) pts with partial response, one (6%) pt had unconfirmed CR. Four (24%) pts had improvement in lymphadenopathy. Median duration of response and median progression‐free survival (PFS) were not reached. All pts are alive. Two (12%) pts discontinued treatment (withdrawal of consent; recurrent LFT abnormalities). The most frequently occurring adverse events of all grades were infusion‐related reactions, neutropenia and fatigue (Table). Summary/Conclusion: In summary, a combination of ENTO and Obin was effective and well tolerated in patients with R/R CLL.