PMID- 30815927
OWN - NLM
STAT- MEDLINE
DCOM- 20190517
LR  - 20210109
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 110
IP  - 5
DP  - 2019 May
TI  - Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or 
      refractory B-cell malignancies in Japan.
PG  - 1686-1694
LID - 10.1111/cas.13983 [doi]
AB  - We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and 
      predictive biomarkers of tirabrutinib, a second-generation, enhanced-selectivity 
      Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory 
      B-cell non-Hodgkin lymphoma (B-cell NHL) and chronic lymphocytic leukemia (CLL). 
      This was an open-label, multicenter, phase I study. Seventeen patients (male 
      N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once 
      daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg 
      twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 
      4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) 
      was the dose-limiting toxicity for 300 mg twice daily. Common adverse events 
      (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed 
      grade >/=3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were 
      frequent. The overall response rate (>/=PR) was 76.5% (13/17 patients), including 4 
      DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 
      mutation, providing promising data for future developments. Of 16 patients with 
      measurable lesions during the screening period, 12 showed >/=50% reductions in 
      tumor diameter. In many patients, the tumor size decreased soon after beginning 
      treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 
      and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 
      1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little 
      accumulation following multiple doses. Tirabrutinib was well tolerated and showed 
      promising efficacy for B-cell NHL/CLL.
CI  - (c) 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Munakata, Wataru
AU  - Munakata W
AUID- ORCID: 0000-0002-4679-0656
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Ando, Kiyoshi
AU  - Ando K
AD  - Department of Hematology and Oncology, Tokai University, Isehara, Japan.
FAU - Hatake, Kiyohiko
AU  - Hatake K
AD  - Department of Hematology and Oncology, Cancer Institute Hospital, Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Fukuhara, Noriko
AU  - Fukuhara N
AD  - Department of Hematology and Rheumatology, Tohoku University Graduate School of 
      Medicine, Sendai, Japan.
FAU - Kinoshita, Tomohiro
AU  - Kinoshita T
AD  - Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.
FAU - Fukuhara, Suguru
AU  - Fukuhara S
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Shirasugi, Yukari
AU  - Shirasugi Y
AD  - Department of Hematology and Oncology, Tokai University, Isehara, Japan.
FAU - Yokoyama, Masahiro
AU  - Yokoyama M
AD  - Department of Hematology and Oncology, Cancer Institute Hospital, Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Ichikawa, Satoshi
AU  - Ichikawa S
AD  - Department of Hematology and Rheumatology, Tohoku University Graduate School of 
      Medicine, Sendai, Japan.
FAU - Ohmachi, Ken
AU  - Ohmachi K
AUID- ORCID: 0000-0002-5530-818X
AD  - Department of Hematology and Oncology, Tokai University, Isehara, Japan.
FAU - Gion, Naokazu
AU  - Gion N
AD  - Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
FAU - Aoi, Arata
AU  - Aoi A
AD  - Department of Oncology Clinical Development Planning, Ono Pharmaceutical Co., 
      Ltd., Osaka, Japan.
FAU - Tobinai, Kensei
AU  - Tobinai K
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
LA  - eng
GR  - Ono Pharmaceutical Co., Ltd/
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
DEP - 20190328
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (CD79 Antigens)
RN  - 0 (CD79A protein, human)
RN  - 0 (CD79B protein, human)
RN  - 0 (Imidazoles)
RN  - 0 (MYD88 protein, human)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - LXG44NDL2T (tirabrutinib)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - CD79 Antigens/genetics
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Imidazoles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Japan
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/genetics
MH  - Male
MH  - Middle Aged
MH  - Myeloid Differentiation Factor 88/genetics
MH  - Neoplasm Recurrence, Local/*drug therapy/genetics
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Pyrimidines/*administration & dosage/adverse effects/pharmacokinetics
MH  - Treatment Outcome
MH  - Tumor Suppressor Protein p53/genetics
PMC - PMC6500982
OTO - NOTNLM
OT  - B-cell malignancy
OT  - B-cell non-Hodgkin lymphoma
OT  - chronic lymphocytic leukemia
OT  - safety
OT  - tirabrutinib
COIS- W. Munakata has received grants from Ono Pharmaceutical Co., Ltd. K. Ando has 
      received grants from Ono Pharmaceutical Co., Ltd. K. Hatake has received grants 
      from Ono Pharmaceutical Co., Ltd. and Chugai Pharmaceutical Co., Ltd. N. Fukuhara 
      has received grants from Ono Pharmaceutical Co., Ltd. T. Kinoshita has received 
      grants and/or personal fees from Chugai Pharmaceutical Co., Ltd., Takeda 
      Pharmaceutical Co., Ltd., Solasia Pharma K.K., Ono Pharmaceutical Co., Ltd., 
      Gilead Sciences, Inc., MSD, Zenyaku Kogyo, Bristol-Myers Squibb, Kyowa Hakko 
      Kirin Co., Ltd., Eisai Co., Ltd., and Janssen Pharmaceutica. S. Fukuhara has 
      received grants from Ono Pharmaceutical Co., Ltd. Y. Shirasugi has received 
      personal fees from Novartis. M. Yokoyama has received grants from Ono 
      Pharmaceutical Co., Ltd. and personal fees from Chugai Pharmaceutical Co., Ltd. 
      S. Ichikawa has received grants from Ono Pharmaceutical Co., Ltd. K. Ohmachi has 
      received grants from Ono Pharmaceutical Co., Ltd. and personal fees from Ono 
      Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Chugai 
      Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Meiji 
      Seika Pharma Co., Ltd. N. Gion is an employee of Ono Pharmaceutical Co., Ltd., 
      and has received personal fees. A. Aoi is an employee of Ono Pharmaceutical Co., 
      Ltd., and has received personal fees. K. Tobinai has received grants and/or 
      personal fees from Ono Pharmaceutical Co., Ltd., Celgene, Zenyaku Kogyo, HUYA 
      Bioscience International LLC, Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., 
      Mundipharma, Janssen Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Chugai 
      Pharmaceutical Co., Ltd., GlaxoSmithKline, and AbbVie Inc.
EDAT- 2019/03/01 06:00
MHDA- 2019/05/18 06:00
PMCR- 2019/05/01
CRDT- 2019/03/01 06:00
PHST- 2018/11/19 00:00 [received]
PHST- 2019/02/06 00:00 [revised]
PHST- 2019/02/20 00:00 [accepted]
PHST- 2019/03/01 06:00 [pubmed]
PHST- 2019/05/18 06:00 [medline]
PHST- 2019/03/01 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - CAS13983 [pii]
AID - 10.1111/cas.13983 [doi]
PST - ppublish
SO  - Cancer Sci. 2019 May;110(5):1686-1694. doi: 10.1111/cas.13983. Epub 2019 Mar 28.