Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.
Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors.
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DOI：
10.1007/s10637-012-9801-2
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发表时间：
2013-02
影响因子：
3.4
通讯作者：
Lechleider, Robert
中科院分区：
文献类型：
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作者：
Annunziata, Christina M;Kohn, Elise C;LoRusso, Patricia;Houston, Nicole D;Coleman, Robert L;Buzoianu, Manuela;Robbie, Gabriel;Lechleider, Robert
背景靶向细胞表面受体EphA 2是一种新型的肿瘤治疗方法，EphA 2在某些实体瘤中高度表达。我们的目的是评估MEDI-547（一种由细胞毒性药物奥瑞他汀（毒素）与人抗EphA 2单克隆抗体（1C 1）连接组成的抗体药物缀合物）在标准疗法复发/难治性实体瘤患者中的安全性特征、最大耐受剂量（MTD）、药代动力学和抗肿瘤活性。方法在这项1期、开放标签研究中，计划剂量递增和剂量扩展队列，患者接受MEDI-547（0.08 mg/kg）静脉输注1小时，每3周一次。结果6例患者接受0.08 mg/kg;均停止治疗。未进行剂量递增。由于治疗相关出血和凝血事件（鼻出血相关，n = 3;鼻衄，n = 2），研究在队列2入组前停止。因此，未探索较低剂量，无法选择MTD。最常报告的治疗相关不良事件（AE）为肝酶升高、血红蛋白降低、食欲下降和鼻衄。3例患者（50%）发生治疗相关严重AE，包括结膜出血、疼痛（导致研究药物停药）、肝脏疾病和出血。最佳缓解包括疾病进展（n = 5; 83.3%）和疾病稳定（n = 1; 16.7%）。血液中毒素与1C 1结合物的解离极轻微或无解离。血清MEDI-547浓度迅速下降，给药后3天下降约70%。在第1次给药后3周进行第2次给药时，在0.08 mg/kg剂量下未观察到MEDI-547蓄积。结论MEDI-547的安全性特征不支持在晚期实体瘤患者中进行进一步的临床研究。
Background Targeting the cell-surface receptor EphA2, which is highly expressed in some solid tumors, is a novel approach for cancer therapy. We aimed to evaluate the safety profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of MEDI-547, an antibody drug conjugate composed of the cytotoxic drug auristatin (toxin) linked to a human anti-EphA2 monoclonal antibody (1C1), in patients with solid tumors relapsed/refractory to standard therapy. Methods In this phase 1, open-label study with planned dose-escalation and dose-expansion cohorts, patients received a 1-h intravenous infusion of MEDI-547 (0.08 mg/kg) every 3 weeks. Results Six patients received 0.08 mg/kg; all discontinued treatment. Dose escalation was not pursued. The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events (hemorrhage-related, n = 3; epistaxis, n = 2). Therefore, lower doses were not explored and an MTD could not be selected. The most frequently reported treatment-related adverse events (AEs) were increased liver enzymes, decreased hemoglobin, decreased appetite, and epistaxis. Three patients (50%) experienced treatment-related serious AEs, including conjunctival hemorrhage, pain (led to study drug discontinuation), liver disorder, and hemorrhage. Best response included progressive disease (n = 5; 83.3%) and stable disease (n = 1; 16.7%). Minimal or no dissociation of toxin from 1C1 conjugate occurred in the blood. Serum MEDI-547 concentrations decreased rapidly, ~70% by 3 days post-dose. No accumulation of MEDI-547 was observed at 0.08 mg/kg upon administration of a second dose 3 weeks following dose 1. Conclusions The safety profile of MEDI-547 does not support further clinical investigation in patients with advanced solid tumors.