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

// John C. Byrd 1 , Stephen Smith 2 , Nina Wagner-Johnston 3 , Jeff Sharman 4 , Andy I. Chen 5 , Ranjana Advani 6 , Bradley Augustson 7 , Paula Marlton 8 , S. Renee Commerford 9 , Kwame Okrah 9 , Lichuan Liu 9 , Elaine Murray 9 , Elicia Penuel 9 , Ashley F. Ward 9 and Ian W. Flinn 10 1 Division of Hematology, Ohio State University Wexner Medical Center, Columbus, OH, USA 2 Division of Medical Oncology, University of Washington, Seattle, WA, USA 3 Division of Oncology, Washington University, St. Louis, MO, USA 4 Willamette Valley Cancer Institute and Research Center, US Oncology, Eugene, OR, USA 5 Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR, USA 6 Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA 7 Sir Charles Gairdner Hospital, Perth, WA, Australia 8 Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia 9 Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA 10 Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, USA Correspondence to: John C. Byrd, email: john.byrd@osumc.edu Keywords: CLL; GCD0853; BTK Received: July 17, 2017 Accepted: September 30, 2017 Published: January 22, 2018 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.