Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma
Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma
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DOI：
10.3324/haematol.2015.133421
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发表时间：
2016-02-01
期刊：
影响因子：
10.1
通讯作者：
Carlile, David J.
中科院分区：
文献类型：
--
作者：
Cartron, Guillaume;Hourcade-Potelleret, Florence;Carlile, David J.
抗CD20单抗(GA101)是一种用于治疗恶性血液病的II型糖工程抗CD20单抗。Obinutuzumab具有与利妥昔单抗不同的作用机制，有可能转化为更好的临床疗效。我们介绍了I/II期Gauguin和I期Gaudi研究的药代动力学和临床数据，这些研究被用来确定正在进行III期评估的obinutuzumab剂量和方案。在第一阶段(高更和高迪)，非霍奇金淋巴瘤患者最多接受9个固定剂量(obinutuzumab 50-2000 mg)。在Gauguin II期，患者接受Obinutuzumab 400/400 mg或1600/800 mg[第一次剂量d1，d8，周期(C)1；第二次剂量d1，C2-C8]。使用探索性图表分析人口统计学因素对药物动力学和药物暴露对肿瘤反应和毒性的影响。通过药代动力学模拟，将1600/800 mg的obinutuzumab血药浓度与1000 mg固定剂量方案(d1，d8和d15，c1；d1，c2-c8)进行比较。CD20抗原量相关因素对Obinutuzumab药代动力学的影响较大，分别为400/400和1600/800 mg。与CD20抗原量无关，1600/800和400/400毫克的血清浓度更高。1600/800与400/400毫克相比，肿瘤缩小更大；不良事件没有显著增加。在基于模型的分析中，固定剂量1000毫克加上额外的C1输注导致的血清浓度与1600/800毫克相似。在这项探索性分析中确定的obinutuzumab 1000 mg固定剂量方案已在一个更大的数据集的全协变量分析中得到确认，并正在进行III期评估。
Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg). In GAUGUIN phase II, patients received obinutuzumab 400/400 mg or 1600/800 mg [first dose day (D)1, D8, cycle (C) 1; second dose D1, C2-C8]. The influence of demographic factors on pharmacokinetics and drug exposure on tumor response and toxicity were analyzed using exploratory graphical analyses. Obinutuzumab serum concentrations with 1600/800 mg were compared with a 1000 mg fixed-dose regimen (D1, D8 and D15, C1; D1, C2-C8) using pharmacokinetic modeling simulations. Factors related to CD20-antigenic mass were more influential on obinutuzumab pharmacokinetics with 400/400 versus 1600/800 mg. Higher serum concentrations were observed with 1600/800 versus 400/400 mg, irrespective of CD20-antigenic mass. Tumor shrinkage was greater with 1600/800 versus 400/400 mg; there was no significant increase in adverse events. Fixed dose 1000 mg with an additional C1 infusion resulted in similar serum concentrations to 1600/800 mg in model-based analyses. The obinutuzumab 1000 mg fixed-dose regimen identified in this exploratory analysis was confirmed in a full covariate analysis of a larger dataset, and is undergoing phase III evaluation.