Phase I study of tirabrutinib (ONO‐4059/GS‐4059) in patients with relapsed or refractory B‐cell malignancies in Japan. Issue 5 (28th March 2019)

• Record Type: Journal Article
• Authors: Munakata, Wataru; Ando, Kiyoshi; Hatake, Kiyohiko; Fukuhara, Noriko; Kinoshita, Tomohiro; Fukuhara, Suguru; Shirasugi, Yukari; Yokoyama, Masahiro; Ichikawa, Satoshi; Ohmachi, Ken; Gion, Naokazu; Aoi, Arata; Tobinai, Kensei
• Is Part Of: Cancer science. Volume 110:Issue 5(2019)
• Page Start: 1686
• Page End: 1694
• Publication Date: 2019-03-28
• Subjects: B‐cell malignancy -- B‐cell non−Hodgkin lymphoma -- chronic lymphocytic leukemia -- safety -- tirabrutinib; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13983
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : This was an open‐label, multicenter, phase I study of tirabrutinib in 17 Japanese patients with relapsed or refractory B‐cell non−Hodgkin lymphoma and chronic lymphocytic leukemia. Patients were enrolled in 4 dose cohorts (160 mg QD [N = 3], 320 mg QD [N = 3], 480 mg QD [N = 4] and 300 mg BID [N = 7]), and tirabrutinib was observed to have linear pharmacokinetics with little accumulation following multiple doses. The most common AE were rash (35.3%) and vomiting (29.4%). The overall response rate was 76.5% (13/17 patients) and the tumor diameter in 12 of 16 patients revealed ≥50% reductions, with 8 patients showing early response within 1 month after beginning treatment among 13 responders who achieved partial response or better; therefore, tirabrutinib was well tolerated and showed promising efficacy.