Department of Medical Oncology, University of Torino, Candiolo Cancer Institute-FPO, IRCCS, Turin.
Department of Medical Oncology, Catholic University of the Sacred Heart, Rome, Italy.
Ann Oncol. 2014 Sep;25(9):1750-1755. doi: 10.1093/annonc/mdu205. Epub 2014 Jun 6.
Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer.
Gemcitabine (1000 mg/m(2) on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab.
From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8-9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%).
Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.
NCT00556023.
Tremelimumab（CP-675,206）是一种完全人源化的单克隆抗体，与 T 细胞上的细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）结合，通过阻断 CTLA4 的负调节信号来刺激免疫系统。与标准化疗联合使用可能会增强抗肿瘤治疗效果。这是一项 I 期、多中心、开放性、非随机剂量递增试验，旨在评估转移性胰腺癌患者联合使用吉西他滨和 tremelimumab 的安全性、耐受性和最大耐受剂量（MTD）。
吉西他滨（1000mg/m2，第 1、8 和 15 天，每 28 天周期）联合静脉注射 tremelimumab（6、10 或 15mg/kg，每 84 天周期第 1 天），最多 4 个周期。前 18 例患者有一个初始的 4 周吉西他滨单药导入期。在首次使用 tremelimumab 后 6 周内评估与 tremelimumab 相关的剂量限制性毒性（DLTs）。
从 2008 年 6 月至 2011 年 8 月，共招募了 34 例患者，他们至少接受了一次 tremelimumab 治疗。在任何剂量下均未观察到与 tremelimumab 相关的 DLTs，即使使用 tremelimumab 的最大剂量（15mg/kg）也是如此。最常见的 3/4 级毒性为乏力（11.8%）和恶心（8.8%）。只有 1 例患者发生严重药物相关事件（腹泻伴脱水）。中位总生存期为 7.4 个月（95%置信区间为 5.8-9.4 个月）。治疗结束时，有 2 例患者获得部分缓解。这 2 例患者均接受了 tremelimumab 15mg/kg 组（n=2/19，10.5%）。
tremelimumab 联合吉西他滨具有良好的安全性和耐受性，值得进一步研究在转移性胰腺癌患者中的应用。
临床试验.gov 注册号：NCT00556023。
