University of Texas M D Anderson Cancer Center, Thoracic Head and Neck Medicine Clinic, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030, USA.
J Clin Oncol. 2010 Jun 10;28(17):2839-46. doi: 10.1200/JCO.2009.25.1991. Epub 2010 May 10.
Apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL)-a member of the tumor necrosis factor cytokine family-induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.
This phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity.
Seventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL.
At the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.
凋亡配体 2/肿瘤坏死因子相关凋亡诱导配体（Apo2L/TRAIL）是肿瘤坏死因子细胞因子家族的成员，通过激活促凋亡死亡受体 DR4 和 DR5 诱导细胞凋亡。重组人 Apo2L/TRAIL（rhApo2L/TRAIL）作为一种癌症治疗方法具有广泛的潜力。据我们所知，这是首次在人体临床试验中评估多种静脉剂量 rhApo2L/TRAIL 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。
这项 I 期、开放性、剂量递增研究用 rhApo2L/TRAIL 治疗剂量范围为 0.5 至 30 mg/kg/d 的晚期癌症患者，对于无肝转移和肝功能正常的患者（队列 1）和有肝转移和正常或轻度异常肝功能的患者（队列 2）进行平行剂量递增。每天给予剂量，连续 5 天，每 3 周重复一个周期。评估包括不良事件（AE）、实验室检查、药代动力学和影像学以评估抗肿瘤活性。
71 名患者接受了平均 18.3 个剂量；7 名患者完成了所有 8 个治疗周期。队列 1 和 2 中 rhApo2L/TRAIL 的 AE 谱相似。最常见的 AE 是疲劳（38%）、恶心（28%）、呕吐（23%）、发热（23%）、贫血（18%）和便秘（18%）。肝酶升高与进行性转移性肝疾病同时发生。2 名滑膜肉瘤（滑膜和未分化）和 1 名软骨肉瘤患者出现与肿瘤快速坏死相关的严重 AE。2 名软骨肉瘤患者对 rhApo2L/TRAIL 有持久的部分缓解。
在测试的方案和剂量范围内，rhApo2L/TRAIL 是安全且耐受良好的。剂量递增达到了与临床前抗肿瘤疗效相关的 rhApo2L/TRAIL 血清峰浓度。
