First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction
First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction
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DOI：
10.1200/jco.2015.63.6530
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发表时间：
2016-04-01
影响因子：
45.3
通讯作者：
Liedtke, Michaela
中科院分区：
文献类型：
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作者：
Gertz, Morie A.;Landau, Heather;Liedtke, Michaela
目的轻链淀粉样变性（Light chain amyloidosis，AL）是由错误折叠的蛋白质聚集而引起的重要器官功能障碍。NEOD 001是一种靶向这些错误折叠蛋白的单克隆抗体。我们报告的中期数据从I/II期剂量递增/扩展研究NEOD 001在AL淀粉样变性和持续性器官功能障碍（NCT 01707264）患者和MethodsPatients谁已经完成了至少一个以前的抗浆细胞定向治疗，有部分血液学反应或更好，并有持续性器官功能障碍接受NEOD 001静脉注射每28天。评价了0.5、1、2、4、8、16和24 mg/kg的剂量水平（3 + 3研究设计）。主要目的是确定最大耐受剂量和未来研究的推荐剂量，并评价安全性/耐受性。次要和探索性的目标包括药代动力学，免疫原性，和器官反应的基础上发表的共识criterions.ResultsTwenty-seven患者参加了7个队列（剂量递增组件）。未报告药物相关严重不良事件（AE）、因药物相关AE而停药、剂量限制性毒性或抗药抗体。最常见的AE为疲乏、上呼吸道感染、咳嗽和呼吸困难。推荐剂量为24 mg/kg。药代动力学支持每28天静脉给药一次。在14例心脏可评价患者中，8例（57%）符合心脏反应标准，6例（43%）病情稳定。15肾可评估的患者，9（60%）符合标准的肾脏反应和6（40%）有稳定的disease.Conclusionmonthly输液NEOD 001是安全的，耐受性良好。推荐的未来剂量为24 mg/kg。器官反应率与以前报道的化疗相比是有利的。第二阶段的扩建正在进行中。已启动全球III期研究（NCT 02312206）。针对错误折叠蛋白的抗体治疗是一种潜在的治疗AL淀粉样变性的新方法。
PurposeLight chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264).Patients and MethodsPatients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria.ResultsTwenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease.ConclusionMonthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.