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

Summary

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 four 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]); four patients had continued tirabrutinib administration as of January 4, 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 four DLBCL patients with no CD79A/B or MYD88 mutations, and one CLL patient with a TP53 mutation, providing promising data for future developments. Twelve of 16 patients with measurable lesions during the screening period 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 was linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B‐cell NHL/CLL.

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