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.

• Authors: Jeff Sharman, Michael Hawkins, Kathryn Kolibaba, Michael Boxer, Leonard Klein, Meihua Wu, Jing Hu, Steve Abella, Chris Yasenchak
• Journal: Blood (Blood) Vol. 125 Issue 15 Pg. 2336-43 (Apr 09 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25696919 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
• Indazoles
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Pyrazines
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase

Topics

• Aged
• Aged, 80 and over
• Disease-Free Survival
• Female
• Humans
• Indazoles (adverse effects, blood, therapeutic use)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, enzymology)
• Male
• Middle Aged
• Protein Kinase Inhibitors (adverse effects, blood, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazines (adverse effects, blood, therapeutic use)
• Syk Kinase