ABSTRACT

Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m² daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.18K322A in patients with osteosarcoma, and of an alternative schedule of weekly hu14.18K322A administration in patients with neuroblastoma or osteosarcoma. Eligible patients with recurrent/refractory osteosarcoma received hu14.13K22A daily x4 every 28 days in a Phase 1 traditional 3 + 3 dose escalation design. Additional patients with osteosarcoma were then enrolled to receive hu14.18K322A once weekly for 4 weeks per course. Patients with recurrent/refractory neuroblastoma were also enrolled on the weekly schedule at 50 mg/m²/dose. Six patients with osteosarcoma treated on the daily schedule received a median of 2 (range 1–6) courses; the recommended daily dose was established as 60 mg/m². Three patients had stable disease (SD) as best overall response. Five patients (3 neuroblastoma, 2 osteosarcoma) enrolled on the weekly schedule received a median of 1 (1–3) course; 2 achieved SD as best overall response. Pain, fever, hematologic toxicities, hyponatremia, and ocular/visual abnormalities were common toxicities among both schedules. Dose-limiting toxicities attributed to hu14.18K322A included anorexia and fatigue (n = 1). Pharmacokinetic profiles were similar between daily and weekly schedules. The recommended dose for patients with osteosarcoma receiving daily hu14.18K322A x4 is 60 mg/m². Patients receiving the weekly schedule experienced similar pharmacokinetics and toxicity profile as the daily schedule.

摘要

Hu14.18K322A是人源化抗GD2单克隆抗体，具有单点突变，可减少补体介导的细胞毒性，最大耐受剂量（MTD）为60 mg / m ²患有复发/难治性神经母细胞瘤的儿童每天4天。我们报告了一项确定骨肉瘤患者hu14.18K322A的MTD和安全性的1期试验的其他结果，以及神经母细胞瘤或骨肉瘤患者每周hu14.18K322A每周给药的替代方案的其他结果。符合条件的复发/难治性骨肉瘤患者在传统的1期3 + 3剂量递增设计中，每28天每天接受hu14.13K22A x4。然后招募其他骨肉瘤患者每周一次接受hu14.18K322A，每疗程4周。复发/难治性神经母细胞瘤患者也按每周计划参加，剂量为50 mg / m ²/剂量。每天接受治疗的6例骨肉瘤患者接受了2个疗程（1-6个疗程）的中位治疗；推荐的每日剂量确定为60 mg / m ²。三名患者具有稳定的疾病（SD）作为最佳总体反应。每周登记的五名患者（3个神经母细胞瘤，2个骨肉瘤）接受了中位疗程1（1-3）个疗程；2获得了SD作为最佳总体响应。在这两种方案中，疼痛，发烧，血液学毒性，低钠血症和眼部/视觉异常是常见的毒性反应。归因于hu14.18K322A的剂量限制性毒性包括厌食症和疲劳（n = 1）。每天和每周的时间表之间的药代动力学特征相似。每天接受hu14.18K322A x4的骨肉瘤患者的推荐剂量为60 mg / m ²。接受每周时间表的患者经历与每日时间表相似的药代动力学和毒性特征。