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.