Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma
Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma
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DOI：
10.1200/jco.2004.08.185
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发表时间：
2004-03-01
影响因子：
45.3
通讯作者：
Sherman, ML
中科院分区：
文献类型：
--
作者：
Atkins, MB;Hidalgo, M;Sherman, ML
目的 评估多剂量 CCI-779（雷帕霉素激酶抑制剂的新型哺乳动物靶标）对晚期难治性肾细胞癌 (RCC) 患者的疗效、安全性和药代动力学。 患者和方法 患者 (n = 111) 被随机分配接受每周 25、75 或 250 mg CCI-779，静脉注射 30 分钟 输液。评估患者的肿瘤反应、肿瘤进展时间、生存率和不良事件。收集血样以确定 CCI-779 药代动力学。结果 CCI-779 在这些晚期 RCC 患者中产生了 7% 的客观缓解率（1 例完全缓解和 7 例部分缓解）和 26% 的轻微缓解。肿瘤进展的中位时间为 5.8 个月，中位生存期为 15.0 个月。所有级别中最常发生的 CCI-779 相关不良事件是斑丘疹 (76%)、粘膜炎 (70%)、乏力 (50%) 和恶心 (43%)。最常见的3级或4级不良事件是高血糖（17%）、低磷血症（13%）、贫血（9%）和高甘油三酯血症（6%）。 CCI-779 剂量水平对毒性和功效均没有显着影响。根据Motzer等人对接受干扰素α治疗的一线转移性肾细胞癌人群使用的标准，将患者回顾性地分为高风险组、中风险组或低风险组。在每个风险组内，每个剂量水平下患者的中位生存期相似。 结论 在晚期 RCC 患者中，CCI-779 显示出抗肿瘤活性并促进生存，并且在测试的三个剂量水平上总体耐受性良好。 (C) 2004 年，美国临床肿瘤学会。
Purpose To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC).Patients and Methods Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics.Results CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779-related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar.Conclusion In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested. (C) 2004 by American Society of Clinical Oncology.