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 - Funding Information:
The authors wish many thanks to all of the patients, their families, and the investigators who participated in this study. This study was funded by Genentech, Inc.,
Funding Information:
Pharmacyclics, and Genentech. Stephen Smith received research funding from Pharmacyclics, Inc., Genentech, Inc., Acerta Pharma, Janssen Research & Development, LLC., Merck and Co, Inc., and Seattle Genetics. Nina Wagner-Johnston served on advisory board and speaker’s bureau for Gilead. Jeff Sharman received research funding and honoria from Acerta, Gilead, Celgene, Pharmacyclics, Janssen, and Abbvie. Andy I. Chen has served on an advisory board for Genentech, Inc. and has received institutional research funding from Genentech, Seattle Genetics, Otsuka and Asana. Ranjana Advani received institutional research funding from Genentech, Inc., Seattle Genetics, Millennium, Merck , Bristol Myers Squibb, Kura, Regeneron, Pharmacyclics, and Jansen; and honorarium for advisory board from Genentech, Inc., Bristol Myers Squibb, Spectrum, and Pharmacyclics. Bradley Augustson has no disclosures. Paula Marlton intermittently provides consultant advisory services to Roche, Novartis, Janssen, Amgen, Gilead, and Pfizer. Ian Flinn received institutional research funding from Acerta, BeiGene, Celgene, Constellation, Curis, Forty Seven, Genentech, Inc., Gilead, ImmunoGen, Infinity, Janssen, TG Therapeutics, and Trillium. Kwame Okrah, Lichuan Liu, Elaine Murray, Elicia Penuel, and S. Renee Commerford are employees of Genentech, Inc., and stock owners of Roche. Ashley Ward was previously employed at Genentech, Inc., and is also a former stock owner of Roche.
Funding Information:
Funding was provided by Mr. and Mrs. Michael Thomas, Four Winds Foundation, Leukemia and Lymphoma Society, and the National Cancer Institute (R01 CA197870, R01 CA183444, R01 CA177292, P01 CA095426, and R35 CA197734) to support BTK resistance work by Dr. Byrd.
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
AN - SCOPUS:85042557720
VL - 9
SP - 13023
EP - 13035
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 16
ER -