First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL

John C. Byrd, Stephen Smith, Nina Wagner-Johnston, Jeff Sharman, Andy Chen, Ranjana Advani, Bradley Augustson, Paula Marlton, S. Renee Commerford, Kwame Okrah, Lichuan Liu, Elaine Murray, Elicia Penuel, Ashley F. Ward, Ian W. Flinn

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.

Original languageEnglish (US)
Pages (from-to)13023-13035
Number of pages13
JournalOncotarget
Volume9
Issue number16
DOIs
StatePublished - Jan 1 2018

Fingerprint

B-Cell Lymphoma
B-Cell Chronic Lymphocytic Leukemia
Non-Hodgkin's Lymphoma
Human Influenza
Mutation
Lymphocytosis
Fatal Outcome
Maximum Tolerated Dose
Agammaglobulinaemia tyrosine kinase
Dizziness
Cough
Causality
Thrombocytopenia
Nausea
Abdominal Pain
Fatigue
Headache
Diarrhea
Pneumonia
Pharmacokinetics

Keywords

  • BTK
  • CLL
  • GCD0853

ASJC Scopus subject areas

  • Oncology

Cite this

Byrd, J. C., Smith, S., Wagner-Johnston, N., Sharman, J., Chen, A., Advani, R., ... Flinn, I. W. (2018). First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget, 9(16), 13023-13035. https://doi.org/10.18632/oncotarget.24310

First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. / Byrd, John C.; Smith, Stephen; Wagner-Johnston, Nina; Sharman, Jeff; Chen, Andy; Advani, Ranjana; Augustson, Bradley; Marlton, Paula; Commerford, S. Renee; Okrah, Kwame; Liu, Lichuan; Murray, Elaine; Penuel, Elicia; Ward, Ashley F.; Flinn, Ian W.

In: Oncotarget, Vol. 9, No. 16, 01.01.2018, p. 13023-13035.

Research output: Contribution to journalArticle

Byrd, JC, Smith, S, Wagner-Johnston, N, Sharman, J, Chen, A, Advani, R, Augustson, B, Marlton, P, Commerford, SR, Okrah, K, Liu, L, Murray, E, Penuel, E, Ward, AF & Flinn, IW 2018, 'First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL', Oncotarget, vol. 9, no. 16, pp. 13023-13035. https://doi.org/10.18632/oncotarget.24310
Byrd, John C. ; Smith, Stephen ; Wagner-Johnston, Nina ; Sharman, Jeff ; Chen, Andy ; Advani, Ranjana ; Augustson, Bradley ; Marlton, Paula ; Commerford, S. Renee ; Okrah, Kwame ; Liu, Lichuan ; Murray, Elaine ; Penuel, Elicia ; Ward, Ashley F. ; Flinn, Ian W. / First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. In: Oncotarget. 2018 ; Vol. 9, No. 16. pp. 13023-13035.
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abstract = "GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15{\%} of patients regardless of causality included fatigue (37{\%}), nausea (33{\%}), diarrhea (29{\%}), thrombocytopenia (25{\%}), headache (20{\%}), and abdominal pain, cough, and dizziness (16{\%}, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23{\%} and -44{\%}). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.",
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