Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors
Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors
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DOI：
10.1093/annonc/mdg248
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发表时间：
2003-06-01
影响因子：
50.5
通讯作者：
Thielert, C
中科院分区：
文献类型：
--
作者：
Punt, CJA;Boni, J;Thielert, C
背景：CCI-779是免疫抑制剂西罗莫司的一种新型酯类，通过抑制细胞周期调节蛋白的翻译发挥细胞抑制作用。我们研究了CCI-779联合亚叶酸钙（LV）和5-氟尿嘧啶（5-FU）治疗晚期实体瘤患者的最大耐受剂量（MTD）和药代动力学（PK）。患者和方法：患者以200 mg/m(2) LV治疗，直接静脉滴注1小时，随后连续静脉滴注5-FU 24小时，第1例患者滴注2000 mg/m(2)，后续患者滴注2600 mg/m(2)。CCI-779在LV之前直接静脉滴注30分钟，从第8天开始，起始剂量为15mg /m(2)，并在随后的患者队列中逐步增加。一个周期包括六周给药，然后休息一周。取血评估CCI-779的PK及其对稳态5-FU暴露的影响。结果：28例患者进入研究，大多数患者的肿瘤类型需要使用5-FU进行治疗。CCI-779剂量分别为15、25、45和75 mg/m(2)。皮肤毒性（皮疹）在所有剂量水平下都很突出。75 mg/m(2) CCI-779的剂量限制毒性（DLT）为口腔炎。随后，45 mg/m(2)的队列扩大到总共15名患者，在该剂量水平下，由于粘膜炎伴肠穿孔，发生了2例与治疗相关的死亡。根据观察到的毒性，决定停止这项研究。在3例胃肠道肿瘤患者中观察到部分反应。CCI-779与5-FU之间无药代动力学相互作用。结论：CCI-779和5-FU/LV的安全性提示药物相关毒性重叠，以相同剂量和方案给药会产生不可接受的毒性，因此不推荐使用。如果CCI-779与5-FU/LV联合使用，则需要探索其他剂量或给药方案。
Background: CCI-779 is a novel ester of the immunosuppressive agent sirolimus that exerts cytostatic effects by the inhibition of the translation of cell-cycle regulatory proteins. We investigated the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CCI-779 in combination with leucovorin (LV) and 5-fluorouracil (5-FU) in patients with advanced solid tumors.Patients and methods: Patients were treated with LV at 200 mg/m(2) as a 1-h i.v. infusion directly followed by continuous 24-h i.v. infusion of 5-FU, in the first patient at 2000 mg/m(2) and in subsequent patients at 2600 mg/m(2). CCI-779 was administered directly prior to LV as a 30-min i.v. infusion at a starting dose of 15 mg/m(2) beginning at day 8 and escalated in subsequent cohorts of patients. One cycle consisted of six weekly administrations followed by 1 week of rest. Blood samples were drawn to assess PK of CCI-779 as well as its effect on steady-state 5-FU exposures.Results: Twenty-eight patients entered the study, the majority having tumor types for which 5-FU is used as a treatment. CCI-779 doses of 15, 25, 45 and 75 mg/m(2) were investigated. Skin toxicity (rash) was prominent at all dose levels examined. Stomatitis was the dose-limiting toxicity (DLT) for 75 mg/m(2) doses of CCI-779. Subsequently the cohort at 45 mg/m(2) was expanded to a total of 15 patients, and at this dose level two treatment-related deaths occurred due to mucositis with bowel perforation. Based on the toxicities observed, it was decided to discontinue the study. Partial responses were observed in three patients with gastrointestinal tumors. No pharmacokinetic interaction between CCI-779 and 5-FU was observed.Conclusions: The safety profiles of CCI-779 and 5-FU/LV suggest an overlap of drug-related toxicities, and the administration of these drugs at these doses and schedule resulted in unacceptable toxicity and therefore cannot be recommended. If CCI-779 is to be used in combination with 5-FU/LV, other doses or schedules of administration will need to be explored.