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 language | English (US) |
|---|---|
| Pages (from-to) | 13023-13035 |
| Number of pages | 13 |
| Journal | Oncotarget |
| Volume | 9 |
| Issue number | 16 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- BTK
- CLL
- GCD0853
ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
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
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.
PY - 2018/1/1
Y1 - 2018/1/1
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
VL - 9
SP - 13023
EP - 13035
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 16
ER -