title: Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies.
abstract: OBJECTIVE
  Survival 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.
  
  
  METHODS
  Patients 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.
  
  
  RESULTS
  Fifty-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.
  
  
  CONCLUSIONS
  Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.
authors.affiliation: Stanford University Medical Center, Stanford, CA 94305-5821, USA. radvani@stanford.edu
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Buggy
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Sharman
authors.forename: Sonali M
authors.initials: SM
authors.lastname: Smith
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Boyd
authors.forename: Barbara
authors.initials: B
authors.lastname: Grant
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Kolibaba
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.forename: Raquel
authors.initials: R
authors.lastname: Izumi
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamdy
authors.forename: Eric
authors.initials: E
authors.lastname: Hedrick
authors.forename: Nathan H
authors.initials: NH
authors.lastname: Fowler
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000284:Administration, Oral; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010880:Piperidines; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016879:Salvage Therapy
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine