PMID- 32639651
OWN - NLM
STAT- MEDLINE
DCOM- 20200914
LR  - 20210403
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 111
IP  - 9
DP  - 2020 Sep
TI  - A multicenter, open-label, phase II study of tirabrutinib (ONO/GS-4059) in 
      patients with Waldenstrom's macroglobulinemia.
PG  - 3327-3337
LID - 10.1111/cas.14561 [doi]
AB  - Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with 
      greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II 
      study of tirabrutinib in patients with treatment-naive (Cohort A) or with 
      relapsed/refractory (Cohort B) Waldenstrom's macroglobulinemia (WM). Patients 
      were treated with tirabrutinib 480 mg once daily. The primary endpoint was major 
      response rate (MRR; >/= partial response). Secondary endpoints included overall 
      response rate (ORR; >/= minor response), time to major response (TTMR), 
      progression-free survival (PFS), overall survival (OS), and safety. In total, 27 
      patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, 
      and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 
      96.2% had the MYD88(L265P) mutation. MRR and ORR were 88.9% and 96.3%, 
      respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). 
      Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 
      6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events 
      (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most 
      AEs classified as grade 1 or 2. Grade >/= 3 AEs included neutropenia (11.1%), 
      lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All 
      bleeding events were grade 1; none were associated with drug-related atrial 
      fibrillation or hypertension. Although the follow-up duration was relatively 
      short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is 
      considered to be highly effective for both untreated and relapsed/refractory WM 
      with a manageable safety profile. (JapicCTI-173646).
CI  - (c) 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Sekiguchi, Naohiro
AU  - Sekiguchi N
AUID- ORCID: 0000-0001-9860-8257
AD  - Department of Hematology, National Hospital Organization Disaster Medical Center, 
      Tachikawa, Japan.
FAU - Rai, Shinya
AU  - Rai S
AD  - Department of Hematology and Rheumatology, Faculty of Medicine, Kindai 
      University, Osakasayama, Japan.
FAU - Munakata, Wataru
AU  - Munakata W
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Suzuki, Kenshi
AU  - Suzuki K
AD  - Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
FAU - Handa, Hiroshi
AU  - Handa H
AD  - Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, 
      Japan.
FAU - Shibayama, Hirohiko
AU  - Shibayama H
AD  - Department of Hematology and Oncology, Osaka University Graduate School of 
      Medicine, Suita, Japan.
FAU - Endo, Tomoyuki
AU  - Endo T
AD  - Department of Hematology, Hokkaido University Hospital, Sapporo, Japan.
FAU - Terui, Yasuhito
AU  - Terui Y
AD  - Department of Hematology Oncology, The Cancer Institute Hospital, Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Iwaki, Noriko
AU  - Iwaki N
AD  - Department of Hematology, Kanazawa University Hospital, Kanazawa, Japan.
FAU - Fukuhara, Noriko
AU  - Fukuhara N
AD  - Department of Hematology and Rheumatology, Tohoku University Graduate School of 
      Medicine, Sendai, Japan.
FAU - Tatetsu, Hiro
AU  - Tatetsu H
AD  - Department of Hematology, Kumamoto University Hospital, Kumamoto, Japan.
FAU - Iida, Shinsuke
AU  - Iida S
AUID- ORCID: 0000-0002-4951-960X
AD  - Department of Hematology and Oncology, Nagoya City University Graduate School of 
      Medical Sciences, Nagoya, Japan.
FAU - Ishikawa, Takayuki
AU  - Ishikawa T
AD  - Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan.
FAU - Shiibashi, Ryota
AU  - Shiibashi R
AD  - Department of Clinical Development, Ono Pharmaceutical Co., LTD., Osaka, Japan.
FAU - Izutsu, Koji
AU  - Izutsu K
AD  - Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
LA  - eng
GR  - Ono Pharmaceutical/
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
DEP - 20200720
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Biomarkers)
RN  - 0 (CXCR4 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 (Receptors, CXCR4)
RN  - LXG44NDL2T (tirabrutinib)
SB  - IM
EIN - Cancer Sci. 2021 Apr;112(4):1669. PMID: 33811719
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers
MH  - Female
MH  - Genotype
MH  - Humans
MH  - Imidazoles/administration & dosage/adverse effects/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Myeloid Differentiation Factor 88/genetics/metabolism
MH  - Neoplasm Grading
MH  - Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic 
      use
MH  - Pyrimidines/administration & dosage/adverse effects/*therapeutic use
MH  - Receptors, CXCR4/genetics/metabolism
MH  - Treatment Outcome
MH  - Waldenstrom Macroglobulinemia/diagnosis/*drug therapy/etiology
PMC - PMC7469793
OTO - NOTNLM
OT  - B-cell malignancy
OT  - BTK inhibitor
OT  - Japanese
OT  - Waldenstrom's macroglobulinemia
OT  - tirabrutinib
COIS- N. Sekiguchi has received research funding from Ono Pharmaceutical. W. Munakata 
      has received research funding from Ono Pharmaceutical. H. Handa has received 
      research funding from Ono Pharmaceutical. H. Shibayama has received honoraria 
      from Takeda, Novartis, Celgene, Janssen, Chugai, and Kyowa Kirin; research 
      funding from Janssen, Ono Pharmaceutical, Celgene, Novartis, Sanofi, AstraZeneca, 
      AbbVie, and Chugai; and scholarship endowment from Astellas, Teijin, Shionogi, 
      Eisai, Sanofi, Taiho, and Nippon Shinyaku. Y. Terui has received honoraria from 
      Chugai, Celgene, Bristol-Myers Squibb, Novartis, Janssen, and Ono Pharmaceutical; 
      and research funding from Bristol-Myers Squibb. N. Fukuhara has received 
      honoraria from Chugai pharma and Kyowa Kirin; and research funding from AbbVie, 
      Bayer, Chugai, Eisai, Gilead Sciences, Incyte, Ono Pharmaceutical, and Solasia. 
      S. Iida has received honoraria from Ono Pharmaceutical, Takeda, Janssen, Celgene, 
      Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi; and research funding from Ono 
      Pharmaceutical, Takeda, Bristol-Myers Squibb, MSD, Janssen, AbbVie, Kyowa Kirin, 
      Chugai, and Sanofi. K. Izutsu has received honoraria from Kyowa Kirin and Eisai; 
      and research funding from Celgene, Chugai, Novartis, Ono, Pharmaceutical, Bayer, 
      Zenyaku Kogyo, Kyowa Kirin, AstraZeneca, Eisai, Incyte, AbbVie, Symbio, Janssen, 
      and Yakult. The other authors have no relationships to disclose. This work was 
      supported by Ono Pharmaceutical. The study sponsor was involved in study design, 
      writing of the report, and in the decision to submit the article for publication. 
      Study drug was provided by Ono Pharmaceutical. All authors had full access to all 
      of the data in the study and had final responsibility for the decision to submit 
      for publication.
EDAT- 2020/07/09 06:00
MHDA- 2020/09/15 06:00
PMCR- 2020/09/01
CRDT- 2020/07/09 06:00
PHST- 2020/05/04 00:00 [received]
PHST- 2020/06/23 00:00 [revised]
PHST- 2020/06/30 00:00 [accepted]
PHST- 2020/07/09 06:00 [pubmed]
PHST- 2020/09/15 06:00 [medline]
PHST- 2020/07/09 06:00 [entrez]
PHST- 2020/09/01 00:00 [pmc-release]
AID - CAS14561 [pii]
AID - 10.1111/cas.14561 [doi]
PST - ppublish
SO  - Cancer Sci. 2020 Sep;111(9):3327-3337. doi: 10.1111/cas.14561. Epub 2020 Jul 20.