This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215–21. ©2017 AACR.

中文翻译：

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靶向 TWEAK 受体的一流人源化单克隆抗体 enavatuzumab 在晚期实体瘤患者中的 1 期研究

这项 I 期研究评估了 enavatuzumab（一种针对 TWEAK 受体的人源化 IgG1 抗体）在晚期实体恶性肿瘤患者中的安全性、MTD、药代动力学 (PK)、药效学和初步抗癌活性。患者每 2 周接受 60 分钟静脉内递增剂量的 enavatuzumab。获得血液用于PK和生物标志物评估。每 8 周按 RECIST 1.0 版进行反应评估的标准 3+3 设计，每个剂量水平招募 3 名患者。以 0.1 至 1.5 mg/kg 的 6 个剂量水平招募了 30 名患者。剂量限制性毒性包括 4 级 (G4) 脂肪酶、G3 胆红素和 G4 淀粉酶升高。肝脏或胰酶升高与药物暴露或肝转移的存在没有明显的相关性。Enavatuzumab 表现出两室线性 PK 模型。估计全身清除率为 23 至 33 毫升/小时，消除半衰期为 7 至 18 天。在第二次给药后，预测的目标有效峰和谷浓度出现在 1.0 mg/kg。没有客观的回应；4例病情稳定。enavatuzumab 的 MTD 为 1.0 mg/kg iv 每 2 周一次。由于肝胰腺实验室异常，不能耐受更高的剂量。在开始进一步的单药或联合策略之前，需要进一步评估肝脏和胰腺酶毒性的机制。摩尔癌症治疗; 17(1); 215-21。©2017 AACR。在第二次给药后，预测的目标有效峰和谷浓度出现在 1.0 mg/kg。没有客观的回应；4例病情稳定。enavatuzumab 的 MTD 为 1.0 mg/kg iv 每 2 周一次。由于肝胰腺实验室异常，不能耐受更高的剂量。在开始进一步的单药或联合策略之前，需要进一步评估肝脏和胰腺酶毒性的机制。摩尔癌症治疗; 17(1); 215-21。©2017 AACR。在第二次给药后，预测的目标有效峰和谷浓度出现在 1.0 mg/kg。没有客观的回应；4例病情稳定。enavatuzumab 的 MTD 为 1.0 mg/kg iv 每 2 周一次。由于肝胰腺实验室异常，不能耐受更高的剂量。在开始进一步的单药或联合策略之前，需要进一步评估肝脏和胰腺酶毒性的机制。摩尔癌症治疗; 17(1); 215-21。©2017 AACR。在开始进一步的单药或联合策略之前，需要进一步评估肝脏和胰腺酶毒性的机制。摩尔癌症治疗; 17(1); 215-21。©2017 AACR。在开始进一步的单药或联合策略之前，需要进一步评估肝脏和胰腺酶毒性的机制。摩尔癌症治疗; 17(1); 215-21。©2017 AACR。