PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

中文翻译：

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抗间皮素抗体-药物偶联物 Anetumab Ravtansine 在晚期或转移性实体瘤中的首次人体、多中心、I 期剂量递增和扩展研究

目的这项 I 期研究，据我们所知是此类首次人体研究，研究了 anetumab ravtansine 的安全性、耐受性、药代动力学和临床活性，这是一种与美登木素生物碱相关的抗间皮素抗体的抗体-药物偶联物DM4，用于已知表达肿瘤分化抗原间皮素的晚期、转移性或复发性实体瘤患者。患者和方法 这项 I 期、开放标签、多中心、剂量递增和剂量扩展的 anetumab ravtansine 研究招募了 148 名患有多种实体瘤类型的成年患者。10 个晚期或转移性实体瘤患者的剂量递增队列 (0.15-7.5 mg/kg) 每 3 周接受一次 anetumab ravtansine，6 个晚期患者的扩展队列，复发性卵巢癌或恶性间皮瘤以最大耐受剂量每 3 周一次、1.8 mg/kg 每周一次和 2.2 mg/kg 每周一次接受 anetumab ravtansine。结果 在 10 个剂量递增队列中招募了 45 名患者。anetumab ravtansine 的最大耐受剂量为每 3 周一次 6.5 mg/kg 或每周一次 2.2 mg/kg。32 名患者被纳入 6.5 mg/kg 每 3 周一次，35 名患者被纳入 1.8 mg/kg 每周一次，36 名患者被纳入 2.2 mg/kg 每周一次扩展队列。最常见的药物相关不良事件是疲劳、恶心、腹泻、厌食、呕吐、周围感觉神经病变和角膜炎/角膜病变。没有与毒品有关的死亡。Anetumab ravtansine 的药代动力学与剂量成正比；平均半衰期为 5.5 天。在148例间皮瘤或卵巢癌、胰腺癌、非小细胞肺癌和乳腺癌患者中，1例完全缓解，11例部分缓解，66例病情稳定。在具有临床活性的患者中检测到高水平的肿瘤间皮素表达。结论 Anetumab ravtansine 表现出可控的安全性和有利的药代动力学特征，在大量预处理的表达间皮素的实体瘤患者中具有令人鼓舞的初步抗肿瘤活性。结果允许在 II 期研究中确定 anetumab ravtansine 的推荐剂量、时间表和患者人群。在具有临床活性的患者中检测到高水平的肿瘤间皮素表达。结论 Anetumab ravtansine 表现出可控的安全性和有利的药代动力学特征，在大量预处理的表达间皮素的实体瘤患者中具有令人鼓舞的初步抗肿瘤活性。结果允许在 II 期研究中确定 anetumab ravtansine 的推荐剂量、时间表和患者人群。在具有临床活性的患者中检测到高水平的肿瘤间皮素表达。结论 Anetumab ravtansine 表现出可控的安全性和有利的药代动力学特征，在大量预处理的表达间皮素的实体瘤患者中具有令人鼓舞的初步抗肿瘤活性。结果允许在 II 期研究中确定 anetumab ravtansine 的推荐剂量、时间表和患者人群。