An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia

Abstract

Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889.

© 2015 by The American Society of Hematology.

Figures

Figure 1

Entospletinib shows greater selectivity for Syk than for R406. The blue circle represents Syk. Kinase activity for entospletinib is illustrated on the left, and kinase activity for R406 is illustrated on the right. Entospletinib is Syk-selective (Syk Kd = 7.6 nM, with only 1 other kinase with a Kd < 100 nM). R406 is nonselective (Syk Kd = 15 nM, with 25 kinases with Kd < 15 nM and 54 additional kinases with Kd < 100 nM).

Figure 2

PFS (N = 41) in CLL subjects.

Figure 3

ORR overall and across subgroups of CLL subjects.

Figure 4

DOR among responding subjects with CLL (N = 25).

Figure 5

Changes in the measured size of lymph nodes from baseline in subjects with CLL (N = 39).

Figure 6

ALC over time in subjects with CLL.

Figure 7

Inhibition of chemokines and cytokines in subjects with CLL after treatment with entospletinib. Serum levels of BCR-mediated chemokines/cytokines, including CCL3/MIP-1α, CCL4/MIP-1β, CCL22/MDC, and tumor necrosis factor α, were measured on day 1 before entospletinib treatment and on days 8 and 29 by Luminex (Life Technologies/Thermo Fisher Scientific, Waltham, MA) immunoassays (n = 40). Entospletinib reduced mean plasma levels of all measured chemokines/cytokines over time (nominal P < .0001).