Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or refractory B-cell malignancies in Japan

Wataru Munakata, Kiyoshi Ando, Kiyohiko Hatake, Noriko Fukuhara, Tomohiro Kinoshita, Suguru Fukuhara, Yukari Shirasugi, Masahiro Yokoyama, Satoshi Ichikawa, Ken Ohmachi, Naokazu Gion, Arata Aoi, Kensei Tobinai

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1686-1694
Number of pages9
JournalCancer science
Issue number5
Publication statusPublished - 2019 May
Externally publishedYes


  • B-cell malignancy
  • B-cell non−Hodgkin lymphoma
  • chronic lymphocytic leukemia
  • safety
  • tirabrutinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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