Weber J, Yang J C, Topalian S L, Parkinson D R, Schwartzentruber D S, Ettinghausen S E, Gunn H, Mixon A, Kim H, Cole D
National Cancer Institute, Surgery Branch, Bethesda, MD 20892.
J Clin Oncol. 1993 Mar;11(3):499-506. doi: 10.1200/JCO.1993.11.3.499.
Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects.
Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously.
Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen.
A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.
基于小鼠模型的临床前证据，即白细胞介素-6（IL-6）介导转移性肿瘤消退，我们对难治性晚期恶性肿瘤患者进行了重组人IL-6的I期研究，以确定其药代动力学、毒性以及可能的免疫和抗肿瘤作用。
重组IL-6每天皮下注射一次，共7天，停药7天，然后再进行7天的IL-6治疗。从3微克/千克/天开始，每3名患者一组逐步增加剂量，前提是前一剂量水平的毒性不是剂量限制性的。根据美国国立癌症研究所通用毒性标准，剂量限制性毒性定义为III级或IV级主要器官毒性，在停止IL-6治疗24小时后未降至II级或更低。患者皮下注射3、10和30微克/千克/天的IL-6进行治疗。
3微克和10微克剂量水平各治疗了3名患者。皮下注射30微克/千克/天IL-6的5名患者中有2名出现III级主要器官毒性，需要停止IL-6治疗。所有患者均出现发热、寒战和轻微疲劳。在10微克/千克和30微克/千克剂量水平的患者中，C反应蛋白（CRP）、纤维蛋白原、血小板计数和淋巴细胞IL-2受体水平显著升高。观察到白蛋白和血红蛋白降低，尤其是在30微克/千克剂量水平。半衰期（T1/2β）为4.2小时，IL-6水平在5小时达到峰值。未观察到抗肿瘤反应。
每日皮下注射IL-6的安全耐受剂量为10微克/千克，30微克/千克时肝毒性和心律失常为剂量限制性毒性。建议进行II期试验，皮下每日注射IL-6至少7天，共两个周期，中间休息一周。然而，肝脏被肿瘤广泛替代且肝功能异常的患者应谨慎接受IL-6治疗。
