人性化的3 f8 Anti-GD2单克隆抗体抗神经母细胞瘤患者的剂量使用集落刺激因子:1期临床试验。

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库什纳BH、张IY Modak年代,Basu EM,罗伯茨党卫军,张NK

人性化的3 f8 Anti-GD2单克隆抗体抗神经母细胞瘤患者的剂量使用集落刺激因子:1期临床试验。

JAMA杂志。2018年12月1;4 (12):1729 - 1735。doi: 10.1001 / jamaoncol.2018.4005。

PubMed ID
30326045 (在PubMed
]
文摘

重要性:嵌合小鼠anti-GD2抗体对神经母细胞瘤是活跃的,但是中和抗体的发展可以妥协的功效。降低免疫原性,hu3F8人性化anti-GD2抗体,是构造。目的:发现最大耐受剂量的hu3F8集落刺激因子。设计、设置和参与者:这第一阶段临床试验使用了一个3 + 3剂量递增设计在一个转诊中心(纽约纪念斯隆凯特林癌症中心,纽约)。参与者参加从2012年12月24日到5月3日,2016年,2018年2月28日,与跟踪和分析。合格标准包括1年以上耐药或复发性神经母细胞瘤前不管数量或种类的治疗。所有57参与者符合资格的标准,根据协议,接受治疗和包含在所有分析。干预措施:治疗周期是每月,如果人类的反人类的抗体仍为负。每个周期由hu3F8注入静脉注射30分钟周一,周三和周五以及集落刺激因子注入皮下接种每日从5天前的最后一天输液。2周期后,hu3F8被增加到最高剂量水平,被证实是安全的。 Main Outcomes and Measures: Toxicity, pharmacokinetics, immunogenicity, and disease response. Results: Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m2), which is more than 2.5 times higher than the standard dosage of 75 mg/m2/cycle or 100 mg/m2/cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-GD2 antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-GD2 antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. Conclusions and Relevance: This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress. Trial Registration: ClinicalTrials.gov identifier: NCT01757626.

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