PMID- 32583848
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20210427
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 23
IP  - 1
DP  - 2021 Jan 30
TI  - Phase I/II study of tirabrutinib, a second-generation Bruton's tyrosine kinase 
      inhibitor, in relapsed/refractory primary central nervous system lymphoma.
PG  - 122-133
LID - 10.1093/neuonc/noaa145 [doi]
AB  - BACKGROUND: The safety, tolerability, efficacy, and pharmacokinetics of 
      tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase 
      inhibitor, were evaluated for relapsed/refractory primary central nervous system 
      lymphoma (PCNSL). METHODS: Patients with relapsed/refractory PCNSL, Karnofsky 
      performance status >/=70, and normal end-organ function received tirabrutinib 320 
      and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) 
      within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under 
      fasted conditions in phase II. RESULTS: Forty-four patients were enrolled; 20, 7, 
      and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, 
      respectively. No DLTs were observed, and the maximum tolerated dose was not 
      reached at 480 mg. Common grade >/=3 adverse events (AEs) were neutropenia (9.1%), 
      lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 
      480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial 
      lung disease). Independent review committee assessed overall response rate (ORR) 
      at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) 
      at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under 
      fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, 
      and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. 
      Median overall survival was not reached. ORR was similar among patients harboring 
      CARD11, MYD88, and CD79B mutations, and corresponding wild types. CONCLUSION: 
      These data indicate favorable efficacy of tirabrutinib in patients with 
      relapsed/refractory PCNSL. TRIAL REGISTRATION: JapicCTI-173646.
CI  - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology.
FAU - Narita, Yoshitaka
AU  - Narita Y
AD  - Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 
      Tokyo, Japan.
FAU - Nagane, Motoo
AU  - Nagane M
AD  - Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
FAU - Mishima, Kazuhiko
AU  - Mishima K
AD  - Department of Neuro-Oncology/Neurosurgery, Saitama Medical University 
      International Medical Center, Saitama, Japan.
FAU - Terui, Yasuhito
AU  - Terui Y
AD  - Department of Hematology and Oncology, Cancer Institute Hospital, Japanese 
      Foundation for Cancer Research, Tokyo, Japan.
FAU - Arakawa, Yoshiki
AU  - Arakawa Y
AD  - Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
FAU - Yonezawa, Hajime
AU  - Yonezawa H
AD  - Department of Neurosurgery, Kagoshima University Hospital, Kagoshima, Japan.
FAU - Asai, Katsunori
AU  - Asai K
AD  - Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan.
FAU - Fukuhara, Noriko
AU  - Fukuhara N
AD  - Department of Hematology and Rheumatology, Tohoku University Graduate School of 
      Medicine, Miyagi, Japan.
FAU - Sugiyama, Kazuhiko
AU  - Sugiyama K
AD  - Department of Medical Oncology, Hiroshima University Hospital, Hiroshima, Japan.
FAU - Shinojima, Naoki
AU  - Shinojima N
AD  - Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan.
FAU - Kitagawa, Junsaku
AU  - Kitagawa J
AD  - Ono Pharmaceutical Co, Ltd, Osaka, Japan.
FAU - Aoi, Arata
AU  - Aoi A
AD  - Ono Pharmaceutical Co, Ltd, Osaka, Japan.
FAU - Nishikawa, Ryo
AU  - Nishikawa R
AD  - Department of Neuro-Oncology/Neurosurgery, Saitama Medical University 
      International Medical Center, Saitama, Japan.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Imidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - LXG44NDL2T (tirabrutinib)
SB  - IM
MH  - Central Nervous System
MH  - *Central Nervous System Neoplasms/drug therapy
MH  - Humans
MH  - Imidazoles
MH  - *Lymphoma, Non-Hodgkin
MH  - Protein Kinase Inhibitors/adverse effects
MH  - Pyrimidines
MH  - Treatment Outcome
PMC - PMC7850159
OTO - NOTNLM
OT  - CARD11
OT  - MYD88
OT  - Bruton's tyrosine kinase
OT  - primary central nervous system lymphoma
OT  - tirabrutinib
EDAT- 2020/06/26 06:00
MHDA- 2021/04/28 06:00
PMCR- 2020/06/25
CRDT- 2020/06/26 06:00
PHST- 2020/06/26 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2020/06/26 06:00 [entrez]
PHST- 2020/06/25 00:00 [pmc-release]
AID - 5862521 [pii]
AID - noaa145 [pii]
AID - 10.1093/neuonc/noaa145 [doi]
PST - ppublish
SO  - Neuro Oncol. 2021 Jan 30;23(1):122-133. doi: 10.1093/neuonc/noaa145.