National Cancer Institute, National Institutes of Health, 10 Center Dr, Building 10 CRC, Room 1W-3750, Bethesda, MD 20892-1104, USA.
J Clin Oncol. 2012 Nov 20;30(33):4141-7. doi: 10.1200/JCO.2012.44.1055. Epub 2012 Oct 15.
Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors.
This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors.
Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response.
Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.
Lexatumumab 是一种针对肿瘤坏死因子相关凋亡诱导配体受体 2 的激动性、全人源单克隆抗体，具有临床前活性的证据表明其对儿科实体瘤有效。
这项 I 期剂量递增研究检查了 lexatumumab 的安全性、耐受性、药代动力学和免疫原性，剂量高达但不超过成人最大耐受剂量（3、5、8 和 10mg/kg），每 2 周给药一次，用于年龄≤21 岁的复发性或进行性实体瘤患者。
24 名患者共接受了 56 个周期的 lexatumumab 治疗，涵盖了所有四个计划的剂量水平。1 名患者出现与辐射回忆一致的 2 级心包炎，1 名患者在第 2 个周期发生 3 级肺炎伴缺氧。5 名患者的疾病稳定了 3 至 24 个周期。没有患者完全或部分缓解，但有几名患者显示出抗肿瘤活性的证据，包括一名患有复发性进行性骨肉瘤的患者，其临床症状和正电子发射断层扫描活性得到缓解，停药后持续了 1 年以上。1 名肝母细胞瘤患者表现出明显的生物标志物反应。
儿科患者耐受每 14 天给予一次的 10mg/kg lexatumumab，这是在成人中确定的最大耐受剂量。该药物似乎在儿科实体瘤中具有一些临床活性，并且可能与放疗联合增强抗肿瘤效果。
