Department of Medicine-Oncology, Stanford University, Stanford, CA.
Department of Clinical Research, Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX.
Ann Oncol. 2010 Feb;21(2):376-381. doi: 10.1093/annonc/mdp292. Epub 2009 Jul 24.
Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity.
This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.
Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.
Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.
Lexatumumab（HGS-ETR2）是一种针对肿瘤坏死因子相关凋亡诱导配体受体 2 的完全人源激动型 mAb，可激活外在凋亡途径，具有很强的临床前抗肿瘤活性。
这项 1 期、剂量递增研究评估了静脉注射每 14 天给予 lexatumumab 在晚期实体瘤患者中的安全性、耐受性、药代动力学（PK）和免疫原性。
31 名患者接受了 5 个剂量水平（0.1-10 mg/kg）的 lexatumumab。大多数（31 名中的 26 名）接受了 4 个或更多周期的治疗。1 名患者在 10 mg/kg 时出现可能与剂量相关的 3 级高淀粉酶血症的毒性。9 名患者疾病稳定。1 名化疗难治性霍奇金病患者出现混合反应。Lexatumumab 的 PK 呈线性，最高可达 10 mg/kg。在 10 mg/kg 剂量下，平均（+/-标准差）t(1/2b)为 13.67 +/- 4.07 天，清除率为 4.95 +/- 1.93 ml/天/kg，V(1)为 45.55 ml/kg，V(ss)为 79.08 ml/kg，表明 lexatumumab 分布在血浆外。未检测到人抗人抗体。
Lexatumumab 可安全地以 10 mg/kg 的剂量每 14 天给药一次。PK 特征支持该方案。在该剂量方案下进一步评估 lexatumumab 是必要的，包括与其他药物联合试验。
