Phase I Trial of a Novel Anti-GD2 Monoclonal Antibody, Hu14.18K322A, Designed to Decrease Toxicity in Children With Refractory or Recurrent Neuroblastoma
Phase I Trial of a Novel Anti-GD2 Monoclonal Antibody, Hu14.18K322A, Designed to Decrease Toxicity in Children With Refractory or Recurrent Neuroblastoma
复制标题
DOI：
10.1200/jco.2013.50.4423
复制
发表时间：
2014-05-10
影响因子：
45.3
通讯作者：
Santana, Victor M.
中科院分区：
文献类型：
--
作者：
Navid, Fariba;Sondel, Paul M.;Santana, Victor M.
目的联合应用抗GD2单抗、ch14.18和细胞因子等免疫治疗，可改善高危神经母细胞瘤患者的预后。然而，这种治疗受到CH14.18相关毒性的限制，这种毒性可能部分通过补体激活来调节。我们报道了一项I期试验的结果，以确定hu14.18K322A的最大耐受量(MTD)、安全性和药代动力学。hu14.18K322A是一种人源化的抗GD2单抗(K322A)，具有单点突变(K322A)，可减少补体依赖的溶解。患者和方法符合条件的难治性或复发性神经母细胞瘤患者每天递增剂量hu14.18K322A，范围从2到70 mg/m(2)，每28天(一个疗程)连续4天。结果38名患者(23名男性，中位年龄，7.2岁)接受了中位两个疗程(范围从1到15)。在36名可评估的患者中，有4名出现了剂量限制的3级或4级毒性，其特征是咳嗽、虚弱、感觉神经病变、厌食、血清病和高血压脑病。在第一疗程中，最常见的非剂量限制的3级或4级毒性是疼痛(68%)和发热(21%)。31例患者中有6例客观有效(4例完全有效，2例部分有效)。HU14.18K322A的一级药动学符合二室线性模型。结论hu14.18K322A初始和晚期半衰期的中位数分别为1.74天和21.1天。结论hu14.18K322A的MTD和推荐的II期剂量为60 mg/m(2)/d，连用4d。不良反应，主要是疼痛，是可控的，并在随后的疗程中得到改善。
Purpose The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis.Patients and Methods Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course).Results Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A (initial phase) and (terminal phase) half-lives were 1.74 and 21.1 days, respectively.Conclusion The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.