title: 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.affiliation: Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, OR;
authors.forename: Jeff
authors.initials: J
authors.lastname: Sharman
authors.affiliation: Gilead Sciences, Inc., Foster City, CA;
authors.forename: Michael
authors.initials: M
authors.lastname: Hawkins
authors.affiliation: Compass Oncology/US Oncology Research, Vancouver, WA;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kolibaba
authors.affiliation: Arizona Oncology, Tucson, AZ; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Boxer
authors.affiliation: Lutheran General Hospital, Niles, IL.
authors.forename: Leonard
authors.initials: L
authors.lastname: Klein
authors.affiliation: Gilead Sciences, Inc., Foster City, CA;
authors.forename: Meihua
authors.initials: M
authors.lastname: Wu
authors.affiliation: Gilead Sciences, Inc., Foster City, CA;
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Gilead Sciences, Inc., Foster City, CA;
authors.forename: Steve
authors.initials: S
authors.lastname: Abella
authors.affiliation: Willamette Valley Cancer Institute and Research Center/US Oncology Research, Springfield, OR;
authors.forename: Chris
authors.initials: C
authors.lastname: Yasenchak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000072377:Syk Kinase; D009025:Morpholines
chemical_list: D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011719:Pyrazines; D000072377:Syk Kinase; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines; C000606896:SYK protein, human