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Ref Type Journal Article
PMID (29560128)
Authors Byrd JC, Smith S, Wagner-Johnston N, Sharman J, Chen AI, Advani R, Augustson B, Marlton P, Renee Commerford S, Okrah K, Liu L, Murray E, Penuel E, Ward AF, Flinn IW
Title First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 9 16 2018 Feb 27 13023-13035 Oncotarget
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Fenebrutinib Fenebrutinib 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Fenebrutinib GDC-0853 BTK inhibitor 36 Fenebrutinib (GDC-0853) is a small molecule inhibitor of BTK, including BTK C481S, which may result in reduced BTK activity, increased cytotoxicity, and antitumor activity (PMID: 30018078, PMID: 29560128).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References