Successful Multifold Dose Escalation of Anti-GD2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study
Successful Multifold Dose Escalation of Anti-GD2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study
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DOI：
10.1200/jco.2010.28.3317
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发表时间：
2011-03-20
影响因子：
45.3
通讯作者：
Cheung, Nai-Kong V.
中科院分区：
文献类型：
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作者：
Kushner, Brian H.;Kramer, Kim;Cheung, Nai-Kong V.
目的疼痛可阻碍3F 8等抗G（D2）单克隆抗体的免疫治疗。热修饰的3F 8（HM 3F 8）缺乏效应子功能，并且可以掩蔽神经上的G（D2）或交叉反应性表位，从而防止后续剂量的未修饰的3F 8激活疼痛纤维。我们假设，3F 8剂量递增是可能的，而不会增加止痛剂的需求，在患者预先与HM 3F 8。患者和方法30例耐药神经母细胞瘤（NB）接受了1至2个周期的3F 8加粒细胞-巨噬细胞集落刺激因子。3F 8剂量从20 mg/m2/d开始，在没有剂量限制性毒性（DLT）的情况下增加20 mg/m2/d。术前用药包括镇痛药、抗组胺药和5分钟HM 3F 8输注。根据既往方案中3F 8 10 mg/m2/d的经验，疼痛DLT定义为2小时内给予超过7剂阿片类药物。将阿片类药物使用与接受3F 8 20 mg/m2/d但未接受HM 3F 8治疗的同期对照组进行比较。评估疾病反应。结果在门诊进行治疗。由于药物供应限制，剂量递增在160 mg/m2/d时停止;即使在该剂量水平下，镇痛剂需求也与历史对照相似，且无DLT。与对照组相比，3F 8剂量水平至80 mg/m2/d的镇痛需求显著降低。结论3F 8的多次剂量递增是可行的。这些发现可以解释为与HM 3F 8可以改变毒性而不减弱抗NB活性的可能性相一致。这种疼痛控制策略可能有助于实现与其他抗GD 2单克隆抗体的剂量递增。J Clin Oncol 29：1168-1174. (C)2011年美国临床肿瘤学会
PurposePain can hinder immunotherapy with anti-G(D2) monoclonal antibodies (MoAbs) like 3F8. Heat-modified 3F8 (HM3F8) lacks effector functions and could mask G(D2) or cross-reactive epitopes on nerves, thereby preventing a subsequent dose of unmodified 3F8 from activating pain fibers. We hypothesized that 3F8 dose escalation is possible without increased analgesic requirements in patients pretreated with HM3F8.Patients and MethodsThirty patients with resistant neuroblastoma (NB) received one to two cycles of 3F8 plus granulocyte-macrophage colony-stimulating factor. 3F8 dosing began at 20 mg/m(2)/d and increased by 20 mg/m2/d in the absence of dose-limiting toxicity (DLT). Premedication included analgesics, antihistamines, and 5-minute infusions of HM3F8. On the basis of experience with 3F8 10 mg/m2/d in prior protocols, the DLT of pain was defined as more than seven doses of opioids administered within 2 hours. Opioid use was compared with a contemporary control group treated with 3F8 20 mg/m2/d but no HM3F8. Disease response was assessed.ResultsTreatment was administered in the outpatient setting. Dose escalation stopped at 160 mg/m2/d because of drug supply limitations; even through this dosage level, analgesic requirements were similar to historical controls, and there were no DLTs. Analgesic requirements at 3F8 dosage levels through 80 mg/m2/d were significantly less compared with controls. Anti-NB activity occurred at all dosages.ConclusionMultifold dose escalation of 3F8 is feasible. The findings can be interpreted as compatible with the possibility that HM3F8 can modify toxicity without blunting anti-NB activity. This pain control strategy may help achieve dose escalation with other anti-GD2 MoAbs. J Clin Oncol 29:1168-1174. (C) 2011 by American Society of Clinical Oncology