利扎布替尼对比安慰剂治疗成人和青少年持续性或慢性免疫性血小板减少症：LUNA 3期III期研究
Rilzabrutinib placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study.
作者信息
Kuter David J, Bussel James B, Ghanima Waleed, Cooper Nichola, Gernsheimer Terry, Lambert Michele P, Liebman Howard A, Tarantino Michael D, Lee Michelle, Guo Hailing, Daak Ahmed
机构信息
Hematology Division, Massachusetts General Hospital, Harvard Medical School, Bartlett Hall 150, 140 Blossom Street, Boston, MA 02114-2603, USA.
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
出版信息
Ther Adv Hematol. 2023 Oct 18;14:20406207231205431. doi: 10.1177/20406207231205431. eCollection 2023.
BACKGROUND
Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 10/L and increase from baseline ⩾20 × 10/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels.
OBJECTIVES
Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP.
DESIGN
Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study.
METHODS AND ANALYSIS
The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 10/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy.
ETHICS
Ethical guidelines and informed consent are followed.
DISCUSSION
The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response.
TRAIL REGISTRATION
ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.
背景
免疫性血小板减少症（ITP）的特征主要是自身抗体介导的血小板破坏和血小板生成受损，导致血小板减少和出血风险增加。其他表现包括血栓形成风险增加和生活质量下降。目前的治疗方法旨在降低血小板破坏率或刺激血小板生成以预防出血。利扎布替尼是一种口服、可逆、强效的布鲁顿酪氨酸激酶抑制剂，专门设计用于治疗免疫介导的疾病，并通过双重作用机制介导其治疗效果：（1）抑制B细胞活化；（2）中断脾脏和肝脏中Fcγ受体对抗体包被细胞的吞噬作用。一项针对ITP患者的利扎布替尼24周剂量探索性I/II期研究显示，血小板反应率为40%（连续2次血小板计数≥50×10⁹/L，且较基线水平增加≥20×10⁹/L，未使用救援药物），且安全性良好，各剂量水平仅出现1/2级短暂不良事件。
目的
评估口服利扎布替尼在成年和青少年持续性或慢性ITP患者中的疗效和安全性。
设计
正在进行的LUNA 3多中心、双盲、安慰剂对照III期研究中对利扎布替尼400mg每日两次进行评估。
方法与分析
主要终点是持久血小板反应，定义为在24周盲法治疗期的最后12周（包括最后6周内至少2次可用测量值），在无救援治疗的情况下，至少三分之二的≥8次每周预定血小板测量值达到血小板计数≥50×10⁹/L。
伦理
遵循伦理准则并获得知情同意。
讨论
LUNA 3试验将进一步研究利扎布替尼在成年和青少年患者中的安全性和疗效，主要目标是解决ITP患者治疗中的一个主要问题：血小板反应的持久性。
试验注册
ClinicalTrials.gov NCT04562766：https://clinicaltrials.gov/ct2/show/NCT04562766；欧盟临床试验注册EudraCT 2020-002063-60：https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60。
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