Abstract

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.

中文翻译：

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第二代Bruton酪氨酸激酶抑制剂替拉鲁替尼在复发/难治性原发性中枢神经系统淋巴瘤的I / II期研究

摘要

背景

评估了第二代高选择性口服布鲁顿酪氨酸激酶抑制剂替拉鲁替尼的安全性，耐受性，疗效和药代动力学，以评估其是否复发/难治性原发性中枢神经系统淋巴瘤（PCNSL）。

方法

复发/难治性PCNSL，Karnofsky行为状态≥70，终末器官功能正常的患者在I期每天接受替拉鲁替尼320和480 mg一次（qd），以评估其28天内使用3 + 3的剂量限制毒性（DLT）剂量递增设计，第二阶段在禁食条件下以480 mg qd服用。

结果

入选了44例患者。20、7和17在空腹情况下分别接受替拉鲁替尼320、480和480 mg。没有观察到DLT，在480 mg时未达到最大耐受剂量。常见的≥3级不良事件（AE）为中性粒细胞减少症（9.1％），淋巴细胞减少，白细胞减少和多形性红斑（各6.8％）。1名每日480 mg的患者发生5级AE（吉氏肺孢子虫）肺炎和间质性肺疾病）。独立审查委员会评估总体缓解率（ORR）为64％：60 mg，5例完全缓解（CR）/未确认的完全缓解（CRu），320 mg，100％，4 CR / CRu，480 mg，53％，6 mg禁食条件下480 mg CR / CRu。在禁食条件下，在320、480和480 mg的情况下，中位无进展生存期分别为2.9个月：2.1、11.1和5.8个月。未达到中位总体生存率。在具有CARD11，MYD88和CD79B突变以及相应野生型的患者中，ORR相似。

结论

这些数据表明替拉鲁替尼在复发/难治性PCNSL患者中具有良好的疗效。

试用注册

JapicCTI-173646。