First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL
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John C. Byrd1, Stephen Smith2, Nina Wagner-Johnston3, Jeff Sharman4, Andy I. Chen5, Ranjana Advani6, Bradley Augustson7, Paula Marlton8, S. Renee Commerford9, Kwame Okrah9, Lichuan Liu9, Elaine Murray9, Elicia Penuel9, Ashley F. Ward9 and Ian W. Flinn10
1Division of Hematology, Ohio State University Wexner Medical Center, Columbus, OH, USA
2Division of Medical Oncology, University of Washington, Seattle, WA, USA
3Division of Oncology, Washington University, St. Louis, MO, USA
4Willamette Valley Cancer Institute and Research Center, US Oncology, Eugene, OR, USA
5Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR, USA
6Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA
7Sir Charles Gairdner Hospital, Perth, WA, Australia
8Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia
9Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA
10Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, USA
John C. Byrd, email: email@example.com
Keywords: CLL; GCD0853; BTK
Received: July 17, 2017 Accepted: September 30, 2017 Published: January 22, 2018
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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