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

Jeff Sharman, Michael Hawkins, Kathryn Kolibaba, Michael Boxer, Leonard Klein, Meihua Wu, Jing Hu, Steve Abella and Chris Yasenchak

Key points

  • Entospletinib is a selective inhibitor of spleen tyrosine kinase, which is implicated in the pathobiology of B-cell lymphoid malignancies.

  • Entospletinib shows clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity.

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 (Syk). This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Subjects received 800 mg of 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, not reached). The objective response rate was 61.0% (95% CI: 44.5%, 75.8%), including three 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.

  • Submitted August 19, 2014.
  • Accepted February 4, 2015.