Cancer Research UK Centre, University of Southampton Faculty of Medicine, Southampton, UK.
Hematology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Lancet Oncol. 2014 Mar;15(3):343-52. doi: 10.1016/S1470-2045(14)70005-1. Epub 2014 Feb 10.
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.
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 (Ctrough) 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.
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 Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/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.
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.
F Hoffmann-La Roche.
静脉注射利妥昔单抗是治疗滤泡性淋巴瘤的主要方法。一种能达到等效利妥昔单抗血清浓度的皮下制剂，可能会提高便利性并节省医疗资源，同时不会降低临床疗效。我们旨在评估固定剂量皮下利妥昔单抗与标准静脉注射利妥昔单抗在 3 周周期中的药代动力学非劣效性。
在我们的两阶段、随机、开放标签、III 期试验中，我们在 23 个国家的 67 个中心招募了未经治疗的 I-IIIa 级、CD20 阳性滤泡性淋巴瘤患者。在第一阶段，我们使用 Pocock 和 Simon 算法将患者 1:1 随机分配至静脉注射利妥昔单抗（375mg/m2）或固定剂量皮下利妥昔单抗（1400mg）组，分层因素包括诱导化疗方案（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。随机分组后，患者在第 1 周期接受一次静脉注射利妥昔单抗诱导剂量，然后在第 2-8 周期进行治疗。在诱导治疗后获得完全或部分缓解的患者继续接受静脉或皮下利妥昔单抗作为每 8 周一次的维持治疗。主要终点是诱导治疗第 7 周期（第 8 周期给药前）时的方案人群中两组间观察到的利妥昔单抗血清谷浓度（Ctrough）比值。患者按治疗方案进行安全性终点分析。目前正在进行第二阶段随访，且已完全入组。本研究在 ClinicalTrials.gov 注册，编号为 NCT01200758。
在 2010 年 2 月 4 日至 2011 年 10 月 21 日期间，我们共招募了 127 名患者。在随机分配至静脉注射利妥昔单抗的 64 名患者中，有 48 名（75%）和随机分配至皮下利妥昔单抗的 63 名患者中，有 54 名（86%）有药代动力学数据。静脉注射组的平均 Ctrough 为 83.13μg/mL，皮下注射组为 134.58μg/mL（比值 1.62，90%CI 1.36-1.94），表明皮下利妥昔单抗具有非劣效性。在静脉注射利妥昔单抗安全性人群中，有 65 名患者（88%）发生了不良事件（30 名[46%]为≥3 级），皮下利妥昔单抗安全性人群中，有 62 名患者（92%）发生了不良事件（29 名[47%]为≥3 级）。两组中最常见的≥3 级不良事件为中性粒细胞减少症（静脉注射组 14 名[22%]患者，皮下注射组 16 名[26%]患者）。与给药相关的不良事件大多为 1-2 级，在静脉注射组中有 21 名（32%）患者，皮下注射组中有 31 名（50%）患者发生。
第一阶段的数据表明，皮下利妥昔单抗的药代动力学特征与静脉注射利妥昔单抗非劣效，且与新的安全性问题无关。第二阶段将提供皮下给药的疗效和安全性数据。
F Hoffmann-La Roche。
