Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study
Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study
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DOI：
10.1016/s1470-2045(14)70005-1
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发表时间：
2014-03-01
期刊：
影响因子：
51.1
通讯作者：
MacDonald, David
中科院分区：
文献类型：
--
作者：
Davies, Andrew;Merli, Francesco;MacDonald, David
背景静脉注射利妥昔单抗是滤泡性淋巴瘤的主要治疗方法。皮下制剂，达到等效的利妥昔单抗血清浓度可能会提高便利性，节省医疗资源，而不牺牲临床活性。我们的目的是评估药代动力学的非劣效性3周周期的固定剂量皮下利妥昔单抗与标准静脉rituximab.Methods在我们的两个阶段，随机，开放标签，3期试验，我们招募了患者与以前未经治疗的1-3a级，CD 20阳性滤泡性淋巴瘤在67个中心在23个国家。在第一阶段，我们按照Pocock和Simon算法将患者1：1随机分配至静脉注射利妥昔单抗（375 mg/m（2））或固定剂量皮下注射利妥昔单抗（1400 mg），并按诱导化疗方案（环磷酰胺、多柔比星、长春新碱、泼尼松或环磷酰胺、长春新碱、泼尼松）、滤泡性淋巴瘤国际预后指数评分和地区分层。随机化后，患者在第1周期接受一次诱导剂量的静脉注射利妥昔单抗，然后分配第2-8周期的治疗。诱导治疗后完全或部分缓解的患者继续静脉或皮下利妥昔单抗维持治疗，每8周一次。主要终点是在符合方案人群中，诱导治疗第7周期（第8周期给药前）时观察到的两组利妥昔单抗血清谷浓度（C谷）比值。对接受治疗的患者进行安全性终点分析。第2阶段的后续行动正在进行中，并完全累积。本研究在ClinicalTrials.gov上注册，编号NCT 01200758。发现2010年2月4日至2011年10月21日期间，我们招募了127名患者。64例随机分配静脉注射利妥昔单抗的患者中有48例（75%）和63例随机分配皮下注射利妥昔单抗的患者中有54例（86%）的药代动力学数据可用。静脉组和皮下组的几何平均C谷值分别为83.13 μ g/mL和134.58 μ g/mL（比值1.62，90% CI 1.36-1.94），显示皮下利妥昔单抗的非劣效性。在静脉注射利妥昔单抗的安全性人群中，65例患者中有57例（88%）出现不良事件（30例[46%] ≥ 3级），皮下注射利妥昔单抗的安全性人群中62例患者中有57例（92%）出现不良事件（29例[47%] ≥ 3级）。两组中最常见的3级或更严重的不良事件是中性粒细胞减少症（静脉组14例[22%]患者，皮下组16例[26%]患者）。与给药相关的不良事件大多为1-2级，发生在21例（32%）静脉组患者和31例（50%）皮下组患者中，解释阶段1的数据显示，皮下利妥昔单抗的药代动力学特征不劣于静脉利妥昔单抗，并且与新的安全性问题无关。第2阶段将提供皮下给药的疗效和安全性数据。
Background Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab.Methods In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1: 1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (C trough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758.Findings Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean C trough was 83.13 mu g/mL in the intravenous group and 134.58 mu g/mL in the subcutaneous group (ratio 1.62, 90% CI 1.36-1.94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade >= 3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade >= 3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group.Interpretation Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration.