Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL.
Adult
Agammaglobulinaemia Tyrosine Kinase
/ antagonists & inhibitors
Aged
Aged, 80 and over
Female
Humans
Leukemia, B-Cell
/ drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell
/ drug therapy
Lymphoma, B-Cell
/ drug therapy
Male
Maximum Tolerated Dose
Middle Aged
Piperidines
/ pharmacokinetics
Protein Kinase Inhibitors
/ therapeutic use
Pyrazoles
/ pharmacokinetics
Pyrimidines
/ pharmacokinetics
Treatment Outcome
Young Adult
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
12 09 2019
12 09 2019
Historique:
received:
02
01
2019
accepted:
24
06
2019
pubmed:
26
7
2019
medline:
24
1
2020
entrez:
26
7
2019
Statut:
ppublish
Résumé
Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%;
Identifiants
pubmed: 31340982
pii: S0006-4971(20)30005-7
doi: 10.1182/blood.2019001160
pmc: PMC6742923
doi:
Substances chimiques
Piperidines
0
Protein Kinase Inhibitors
0
Pyrazoles
0
Pyrimidines
0
zanubrutinib
AG9MHG098Z
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
BTK protein, human
EC 2.7.10.2
Banques de données
ClinicalTrials.gov
['NCT02343120']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
851-859Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology.
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