利妥昔单抗皮下与静脉给药作为滤泡性淋巴瘤维持治疗的比较：来自两阶段、Ib 期研究的结果。
Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study.
机构信息
Antonio Salar, Hospital del Mar, Barcelona, Spain; Irit Avivi, Rambam Medical Center, Haifa; Ofer Shpilberg, Tel Aviv University, Tel Aviv, Israel; Beate Bittner, Olivier Catalani, Florence Hourcade-Potelleret, and Pakeeza Sayyed, F. Hoffmann-La Roche, Basel, Switzerland; Reda Bouabdallah, Institut Paoli-Calmettes, Marseille, France; Mike Brewster and Christine McIntyre, Roche Products, Welwyn Garden City; George Follows, Addenbrooke's Hospital, University of Cambridge, Cambridge; Andrew Haynes, Nottingham City Hospital, Nottingham, United Kingdom; Andrea Janikova, University Hospital Brno, Brno, Czech Republic; Jean-François Larouche, Hôpital de l'Enfant-Jésus, Centre Hospitalier Universitaire de Québec, Québec, Canada; Michael Pedersen, Herlev Hospital, Herlev, Denmark; Juliana Pereira, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; and Gayane Tumyan, Russian Cancer Research Center, Moscow, Russia.
出版信息
J Clin Oncol. 2014 Jun 10;32(17):1782-91. doi: 10.1200/JCO.2013.52.2631. Epub 2014 May 12.
PURPOSE
This two-stage phase IB study investigated the pharmacokinetics and safety of subcutaneous (SC) versus intravenous (IV) administration of rituximab as maintenance therapy in follicular lymphoma.
PATIENTS AND METHODS
In stage 1 (dose finding), 124 patients who responded to rituximab induction were randomly assigned to SC rituximab (375 mg/m2, 625 mg/m2, or an additional group at 800 mg/m2) or IV rituximab (375 mg/m2). The objective was to determine an SC dose that would yield a rituximab serum trough concentration (Ctrough) in the same range as that of IV rituximab. In stage 2, 154 additional patients were randomly assigned (1:1) to SC rituximab (1,400 mg) or IV rituximab (375 mg/m2) given at 2- or 3-month intervals. The objective was to demonstrate noninferior rituximab Ctrough of SC rituximab relative to IV rituximab 375 mg/m2.
RESULTS
Stage 1 data predicted that a fixed dose of 1,400 mg SC rituximab would result in a serum Ctrough in the range of that of IV rituximab. Noninferiority (ie, meeting the prespecified 90% CI lower limit of 0.8) was then confirmed in stage 2, with geometric mean Ctrough SC:Ctrough IV ratios for the 2- and 3-month regimens of 1.24 (90% CI, 1.02 to 1.51) and 1.12 (90% CI, 0.86 to 1.45), respectively. Overall safety profiles were similar between formulations (in stage 2, 79% of patients experienced one or more adverse events in each group). Local administration-related reactions (mainly mild to moderate) occurred more frequently after SC administration.
CONCLUSION
The fixed dose of 1,400 mg SC rituximab predicted by using stage 1 results was confirmed to have noninferior Ctrough levels relative to IV rituximab 375 mg/m2 dosing during maintenance, with a comparable safety profile. Additional investigation will be required to determine whether the SC route of administration for rituximab provides equivalent efficacy compared with that of IV administration.
目的
本两阶段 Ib 期研究旨在考察滤泡性淋巴瘤患者接受利妥昔单抗皮下（SC）给药与静脉（IV）给药作为维持治疗的药代动力学和安全性。
患者和方法
在第 1 阶段（剂量确定）中，124 例对利妥昔单抗诱导有反应的患者被随机分配至 SC 利妥昔单抗（375mg/m2、625mg/m2 或加一组 800mg/m2）或 IV 利妥昔单抗（375mg/m2）组。目的是确定 SC 剂量，使利妥昔单抗血清谷浓度（Ctrough）与 IV 利妥昔单抗的浓度范围相同。在第 2 阶段，另外 154 例患者被随机分配（1:1）至 SC 利妥昔单抗（1400mg）或 IV 利妥昔单抗（375mg/m2），每 2 或 3 个月给药一次。目的是证明 SC 利妥昔单抗相对于 IV 利妥昔单抗 375mg/m2 的非劣效性 Ctrough。
结果
第 1 阶段的数据预测，固定剂量的 1400mg SC 利妥昔单抗将导致血清 Ctrough 处于 IV 利妥昔单抗的范围内。第 2 阶段证实了非劣效性（即符合预先指定的 90%CI 下限 0.8），2 个月和 3 个月方案的几何均数 Ctrough SC:Ctrough IV 比值分别为 1.24（90%CI，1.02 至 1.51）和 1.12（90%CI，0.86 至 1.45）。两种制剂的总体安全性特征相似（在第 2 阶段，每组均有 79%的患者发生 1 次或 1 次以上不良事件）。与 SC 给药相关的局部给药反应（主要为轻度至中度）在 SC 给药后更为常见。
结论
使用第 1 阶段结果预测的固定剂量 1400mg SC 利妥昔单抗被证实与 IV 利妥昔单抗 375mg/m2 剂量维持治疗时的 Ctrough 水平具有非劣效性，安全性特征相当。需要进一步研究来确定利妥昔单抗 SC 给药途径是否与 IV 给药具有等效疗效。
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