title: Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies.
abstract: In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (≥ 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose-dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL.
  
  
  BACKGROUND
  NCT01704963.
authors.affiliation: Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan. ktobinai@ncc.go.jp.
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.|Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Munakata
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Morishita
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital/Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ushijima
authors.affiliation: Janssen Pharmaceutical K.K., Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Takahara
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
keywords: B cell malignancies; Covalent BTK inhibitor; Ibrutinib; Japanese; Safety