PMID- 29560128 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 9 IP - 16 DP - 2018 Feb 27 TI - First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. PG - 13023-13035 LID - 10.18632/oncotarget.24310 [doi] 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. FAU - Byrd, John C AU - Byrd JC AD - Division of Hematology, Ohio State University Wexner Medical Center, Columbus, OH, USA. FAU - Smith, Stephen AU - Smith S AD - Division of Medical Oncology, University of Washington, Seattle, WA, USA. FAU - Wagner-Johnston, Nina AU - Wagner-Johnston N AD - Division of Oncology, Washington University, St. Louis, MO, USA. FAU - Sharman, Jeff AU - Sharman J AD - Willamette Valley Cancer Institute and Research Center, US Oncology, Eugene, OR, USA. FAU - Chen, Andy I AU - Chen AI AD - Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR, USA. FAU - Advani, Ranjana AU - Advani R AD - Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, USA. FAU - Augustson, Bradley AU - Augustson B AD - Sir Charles Gairdner Hospital, Perth, WA, Australia. FAU - Marlton, Paula AU - Marlton P AD - Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia. FAU - Renee Commerford, S AU - Renee Commerford S AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Okrah, Kwame AU - Okrah K AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Liu, Lichuan AU - Liu L AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Murray, Elaine AU - Murray E AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Penuel, Elicia AU - Penuel E AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Ward, Ashley F AU - Ward AF AD - Early Clinical Development, Genentech, Inc., South San Francisco, CA, USA. FAU - Flinn, Ian W AU - Flinn IW AD - Blood Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, USA. LA - eng GR - R01 CA197870/CA/NCI NIH HHS/United States GR - R01 CA177292/CA/NCI NIH HHS/United States GR - R01 CA183444/CA/NCI NIH HHS/United States GR - P01 CA095426/CA/NCI NIH HHS/United States GR - P30 CA016058/CA/NCI NIH HHS/United States GR - R35 CA197734/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20180122 PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 EIN - Oncotarget. 2019 Jun 04;10(38):3827-3830. PMID: 31217910 PMC - PMC5849192 OTO - NOTNLM OT - BTK OT - CLL OT - GCD0853 COIS- CONFLICTS OF INTEREST John C. Byrd is a unpaid consultant to Acerta, Gilead, 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. EDAT- 2018/03/22 06:00 MHDA- 2018/03/22 06:01 PMCR- 2018/02/27 CRDT- 2018/03/22 06:00 PHST- 2017/07/17 00:00 [received] PHST- 2017/09/30 00:00 [accepted] PHST- 2018/03/22 06:00 [entrez] PHST- 2018/03/22 06:00 [pubmed] PHST- 2018/03/22 06:01 [medline] PHST- 2018/02/27 00:00 [pmc-release] AID - 24310 [pii] AID - 10.18632/oncotarget.24310 [doi] PST - epublish SO - Oncotarget. 2018 Jan 22;9(16):13023-13035. doi: 10.18632/oncotarget.24310. eCollection 2018 Feb 27.