Mahalingam Devalingam, Patel Manish R, Sachdev Jasgit C, Hart Lowell L, Halama Niels, Ramanathan Ramesh K, Sarantopoulos John, Völkel Dirk, Youssef Ashraf, de Jong Floris A, Tsimberidou Apostolia Maria
University of Texas Health Science Center, San Antonio, TX, USA.
Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
Br J Clin Pharmacol. 2020 Sep;86(9):1836-1848. doi: 10.1111/bcp.14289. Epub 2020 Apr 12.
Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation.
In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent.
Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients).
Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.
临床前证据表明，氧化型巨噬细胞移动抑制因子（oxMIF）可能参与致癌过程。这项1期研究（NCT01765790）采用“3+3”剂量递增法，评估了oxMIF抑制剂伊马鲁单抗在晚期癌症患者中的安全性、耐受性、药代动力学和抗肿瘤活性。
在方案1中，实体瘤患者每2周静脉注射1至50mg/kg的剂量。在方案2中，转移性结直肠癌、非小细胞肺癌或卵巢癌患者每周静脉注射10或25mg/kg的剂量（1个周期=28天）。治疗持续至疾病进展、出现不可接受的毒性、剂量限制性毒性或患者撤回同意书。
68名入组患者中有50名接受了伊马鲁单抗治疗。最常见的治疗相关不良事件（TRAEs）包括疲劳（10%）和呕吐（6%）；发生了4例3级严重TRAEs（2名患者）。剂量限制性毒性为过敏性肺泡炎（1名患者，每2周50mg/kg）。最大耐受剂量和生物活性剂量分别为每2周37.5mg/kg和每周10mg/kg。在39名接受评估的患者中，13名病情稳定（8名患者病情稳定≥4个月）。
伊马鲁单抗在晚期实体瘤患者中的最大耐受剂量为每2周37.5mg/kg，生物活性剂量为每周10mg/kg。进一步的研究将有助于明确oxMIF作为癌症治疗靶点的作用。
