TY - JOUR
T1 - First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL
AU - Byrd, John C.
AU - Smith, Stephen
AU - Wagner-Johnston, Nina
AU - Sharman, Jeff
AU - Chen, Andy I.
AU - Advani, Ranjana
AU - Augustson, Bradley
AU - Marlton, Paula
AU - Commerford, S. Renee
AU - Okrah, Kwame
AU - Liu, Lichuan
AU - Murray, Elaine
AU - Penuel, Elicia
AU - Ward, Ashley F.
AU - Flinn, Ian W.
N1 - Publisher Copyright:
© Byrd et al.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - BTK
KW - CLL
KW - GCD0853
UR - http://www.scopus.com/inward/record.url?scp=85042557720&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042557720&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24310
DO - 10.18632/oncotarget.24310
M3 - Article
C2 - 29560128
AN - SCOPUS:85042557720
SN - 1949-2553
VL - 9
SP - 13023
EP - 13035
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -