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

Abstract

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.

• Authors: 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
• Journal: Cancer science (Cancer Sci) Vol. 110 Issue 5 Pg. 1686-1694 (May 2019) ISSN: 1349-7006 [Electronic] England
• PMID: 30815927 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• CD79 Antigens
• CD79A protein, human
• CD79B protein, human
• Imidazoles
• MYD88 protein, human
• Myeloid Differentiation Factor 88
• Protein Kinase Inhibitors
• Pyrimidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• tirabrutinib

Topics

• Aged
• Aged, 80 and over
• CD79 Antigens (genetics)
• Drug Administration Schedule
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Japan
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics)
• Male
• Middle Aged
• Myeloid Differentiation Factor 88 (genetics)
• Neoplasm Recurrence, Local (drug therapy, genetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Tumor Suppressor Protein p53 (genetics)