Document Detail

Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies.
MedLine Citation:
PMID:  23045577     Owner:  NLM     Status:  Publisher    
PURPOSESurvival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. PATIENTS AND METHODSPatients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles.ResultsFifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. CONCLUSIONIbrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.
Ranjana H Advani; Joseph J Buggy; Jeff P Sharman; Sonali M Smith; Thomas E Boyd; Barbara Grant; Kathryn S Kolibaba; Richard R Furman; Sara Rodriguez; Betty Y Chang; Juthamas Sukbuntherng; Raquel Izumi; Ahmed Hamdy; Eric Hedrick; Nathan H Fowler
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Journal of clinical oncology : official journal of the American Society of Clinical Oncology     Volume:  -     ISSN:  1527-7755     ISO Abbreviation:  J. Clin. Oncol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8309333     Medline TA:  J Clin Oncol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Ranjana H. Advani, Stanford University Medical Center, Stanford; Joseph J. Buggy, Sara Rodriguez, Betty Y. Chang, Juthamas Sukbuntherng, Raquel Izumi, Ahmed Hamdy, and Eric Hedrick, Pharmacyclics, Sunnyvale, CA; Jeff P. Sharman, US Oncology, Willamette Valley Cancer Center, Springfield, OR; Sonali M. Smith, University of Chicago, Chicago, IL; Thomas E. Boyd, US Oncology, Yakima Valley Memorial Hospital, Yakima; Kathryn S. Kolibaba, US Oncology, Northwest Cancer Specialists, Vancouver, WA; Barbara Grant, University of Vermont, Burlington, VT; Richard R. Furman, Weill Cornell Medical College, New York, NY; and Nathan H. Fowler, MD Anderson Cancer Center, Houston, TX.
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