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

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.

Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.

Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up. Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions. Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment. Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib.

Background: Tirabrutinib, a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS. Results: Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Conclusions: Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

Long-term safety profile of tirabrutinib: final results of a Japanese Phase I study in patients with relapsed or refractory B-cell malignancies.

Tirabrutinib is a Bruton's tyrosine kinase inhibitor for treating B-cell malignancies. We report the final results of a Phase I study of tirabrutinib in 17 Japanese patients with B-cell malignancies. Patients were administered tirabrutinib at a dose of 160 mg, 320 mg, or 480 mg once daily, or 300 mg twice daily (N = 3, 3, 4, and 7, respectively). Three patients continued tirabrutinib until study completion (November 30, 2020). Adverse events (AEs) occurred in all 17 patients, with Grade 3-4 AEs in 8 (47.1%), serious AEs in 7 (41.2%), drug-related AEs in 16 (94.1%), and Grade 3-4 drug-related AEs in 6 (35.3%). Drug-related AEs reported in 3 or more patients were rash, vomiting, neutropenia, arthralgia, and malaise. One additional serious AE (benign neoplasm of the lung, unrelated to tirabrutinib) occurred after the previous data cutoff (January 4, 2018). Tirabrutinib administration and response assessment were continued for over 4 years in 4 patients. The overall response rate was 76.5% (13/17 patients). The median (range) time to response and duration of response were 0.9 (0.9-5.9) months and 2.59 (0.08-5.45) years, respectively. These findings demonstrate the long-term safety and efficacy of tirabrutinib in Japanese patients with B-cell malignancies.Clinical trial registration: JapicCTI-142682 ( http://www.clinicaltrials.jp/ ).

Phase I/II study of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma.

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.

3-O-ß-D-Glucopyranosyltheobroxide from Aerial Parts of Cowpea (Vigna unguiculata).

Theobroxide has been isolated from culture filtrates of Lasiodiplodia theobromae as a potato tuber-inducing compound. In this study, the metabolism of theobroxide was investigated using cowpea as an experimental model and [2H3-7]theobroxide as a substrate for analyzing a metabolite, which revealed that theobroxide applied exogenously to the roots was converted into 3-O-ß-D-glucopyranosyltheobroxide.