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In an open-label, phase II study, we evaluated entospletinib monotherapy for patients with relapsed or refractory diffuse large B-cell lymphoma. Entospletinib had limited activity in these patients. Seventy-four percent of the patients experienced a grade ≥ 3 adverse event. Treatment was interrupted in 42% of the patients, and the drug was discontinued in 19% of the patients.Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. Entospletinib monotherapy was evaluated in a multicenter, phase II study of subjects with relapsed or refractory B-cell malignancy.The study included 43 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The participants received 800 mg of the original, monomesylate formulation of entospletinib twice daily as a starting dose; the doses could be reduced because of toxicity throughout the study.No patient achieved a complete or partial response, 5 patients (12%) had stable disease, and 26 patients (60%) had progressive disease. Progression-free survival (PFS) at 16 weeks was 3.6% (95% confidence interval [CI], 0.3%-15.3%), and the median PFS was 1.5 months (95% CI, 1-1.7 months). The independent review committee–assessed nodal response for 27 evaluable patients showed a reduced tumor burden in 6 patients (22%). The median duration of entospletinib treatment for these 6 patients was 9 weeks (range, 3-24 weeks). One patient (4%) had a decrease of ≥ 50% in the sum of the product of the nodal diameters. The treatment-emergent adverse events occurring in ≥ 20% of the cohort were fatigue, nausea, decreased appetite, constipation, dyspnea, diarrhea, dehydration, cough, insomnia, and peripheral edema. The common laboratory abnormalities occurring in ≥ 20% of the subjects were lymphocytopenia, anemia, creatinine (chronic kidney disease), increased aspartate aminotransferase, hypoalbuminemia, total bilirubin, hyponatremia, leukopenia, increased alanine aminotransferase, increased alkaline phosphatase, and hyperglycemia.Entospletinib monotherapy at 800 mg twice daily demonstrated limited activity in patients with advanced, relapsed DLBCL.