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An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma.

ABSTRACT: BACKGROUND: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. PATIENTS AND METHODS: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. RESULTS: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. CONCLUSION:Entospletinib monotherapy at 800 mg twice daily demonstrated limited activity in patients with advanced, relapsed DLBCL.

SUBMITTER: Burke JM

PROVIDER: S-EPMC6857170 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma.

Burke John M JM Shustov Andrei A Essell James J Patel-Donnelly Dipti D Yang Jay J Chen Robert R Ye Wei W Shi Wen W Assouline Sarit S Sharman Jeff J

Clinical lymphoma, myeloma & leukemia 20180606 8

<h4>Background</h4>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.<h4>Patients and methods</h4>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 ...[more]

PMID: 29934062

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Project description:Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

Dataset Information

An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma.

Publications

An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma.

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