Phase 2 Trial of GS-9973, a Selective Syk Inhibitor, in Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma
Spleen tyrosine kinase (Syk) is an essential mediator of B-cell receptor signaling in normal and transformed B-cells. GS-9973 is an orally bioavailable, small-molecule, selective inhibitor of Syk.
In this phase 2 trial, Sharman and colleagues enrolled patients with chronic lymphocytic leukemia ([CLL], 1 cohort of 40 patients) or non-Hodgkin lymphoma ([NHL], 4 cohorts of 40 patients each). All patients were treated with GS-9973 (800 mg twice daily). All patients with CLL/SLL were heavily pretreated; 100% of patients received an anti-CD20 antibody, 89% had received an alkylating agent, (59% had bendamustine) and 72% had received fludarabine. Tumor imaging was conducted at weeks 8, 16, 24, and every 12 weeks thereafter. Response was evaluated according to the standard criteria for CLL.
Of the 29 patients evaluable for response at week 8, 20 patients (69%), including those with poor prognostic features, achieved nodal responses, defined as 50% or greater reduction in adenopathy.
The safety analysis included 78 patients who completed at least 4 weeks of treatment. Overall, GS-9973 was well tolerated. Grade 3 or higher fatigue was reported in 5 patients (6%), and reversible grade 3 or higher transaminase elevations were reported in 9 patients (12%). In addition, eleven patients (14%) discontinued treatment because of adverse events. Of the 78 patients, 4 patients died during the study period; 3 patients died of progressive disease and 1 patient died of septic shock.
Sharman and colleagues concluded that GS-9973, administered at 800 mg twice daily, was generally well tolerated. Study of GS-9973 continues in CLL and other hematologic malignancies.
Sharman JP, Klein L, Boxer M, et al. Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL) and non-hodgkin lymphoma (NHL). Poster presented at: American Society of Hematology (ASH) 2013 Annual Meeting; December 6-10, 2013; New Orleans, LA. Abstract 1634.