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

John M. Burke, Andrei Shustov, James Essell, Dipti Patel-Donnelly, Jay Yang, Robert Chen, Wei Ye, Wen Shi, Sarit Assouline, Jeff Sharman

Research output: Contribution to journalArticle

Abstract

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. 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.

Original languageEnglish (US)
JournalClinical Lymphoma, Myeloma and Leukemia
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Lymphoma, Large B-Cell, Diffuse
Syk Kinase
6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
Disease-Free Survival
Confidence Intervals
Hypoalbuminemia
Lymphopenia
Hyponatremia
Leukopenia
Sleep Initiation and Maintenance Disorders
Appetite
Constipation
Aspartate Aminotransferases
Tumor Burden
Alanine Transaminase
Chronic Renal Insufficiency
Dehydration
Bilirubin
Cough
Hyperglycemia

Keywords

  • B-cell receptor signaling inhibitors
  • DLBCL
  • Hematologic malignancies
  • Monotherapy
  • Syk

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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.; Shustov, Andrei; Essell, James; Patel-Donnelly, Dipti; Yang, Jay; Chen, Robert; Ye, Wei; Shi, Wen; Assouline, Sarit; Sharman, Jeff.

In: Clinical Lymphoma, Myeloma and Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

Burke, John M. ; Shustov, Andrei ; Essell, James ; Patel-Donnelly, Dipti ; Yang, Jay ; Chen, Robert ; Ye, Wei ; Shi, Wen ; Assouline, Sarit ; Sharman, Jeff. / An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma. In: Clinical Lymphoma, Myeloma and Leukemia. 2018.
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abstract = "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. 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.",
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AU - Essell, James

AU - Patel-Donnelly, Dipti

AU - Yang, Jay

AU - Chen, Robert

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AU - Shi, Wen

AU - Assouline, Sarit

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N2 - 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. 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.

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