Influence of Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype on Clinical Outcomes and Pharmacokinetics in Chinese Patients With Metastatic Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 583
- 试验地点
- 1
- 主要终点
- Incidence of toxicity, especially neutropenia and diarrhea
研究概览
简要总结
The purpose of this study is to investigate the influence of dose selection of CPT-11 on toxicity, response and pharmacokinetics according to UGT1A1 genotype in colorectal cancer patients.
详细描述
Genetic polymorphisms of UGTs result in reduced enzyme activity and increased toxicity. UGT1A1*28 and UGT1A1*6 are reported to increase CPT-11-related toxicity in Asian patients. Moreover, the area under concentration curve (AUC) ratio of SN-38G to SN-38 is decreased in Asian patients having UGT1A1 *28 or UGT1A1*6. This implicated that the current standard dose of CPT-11 would be overdosing for homozygous UGT1A1*28/*28, *6/*6 or *28/*6 patients.
The study is designed to investigate the role of prospectively dose reduction of CPT-11 in toxicity, tumor response and pharmacokinetics for homozygous UGT1A1 patients, and compare these parameters to standard dose of CPT-11 for wild-type, heterozygous or homozygous UGT1A1 patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
- •At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
- •Aged 18 years or older
- •ECOG performance status of ≤
- •Anticipated life expectancy of ≥ 3 months.
- •UGT1A1 genotype tested. Categorized into Wild (UGT1A1*1/*1), Hetero (UGT1A1*1/ *28, UGT1A1*1/ *6), and Homo (UGT1A1*28/*28, UGT1A1*6/*6, UGT1A1*28/*6).
- •Adequate organ function, including bone marrow, kidney and liver.
- •ANC ≥ 1.5×109/L and hemoglobin ≥ 9g/dL and platelet count ≥ 100×109/L
- •Serum total bilirubin ≤ 1.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN, Serum ALT and AST ≤ 2.5 x ULN (Serum ALT and AST ≤ 5 x ULN, if liver metastases are present)
- •Serum creatinine ≤ 1.5 x ULN or CLcr > 60 ml/min
- •Written informed consent can be obtained prior to their participation in the trial.
排除标准
- •Pregnant or breast feeding women.
- •Subjects who have previously received CPT-11 treatment.
- •Serious concurrent complication, severe active infection.
- •Subjects with chronic diarrhea, acute or sub acute Intestinal obstruction.
- •Subjects with uncontrolled CNS metastasis or epilepsia or severe psychiatric disorders.
- •Subjects who are regarded to be unsuitable for this trial by the investigator.
- •Subjects who are participating in other clinical trials.
研究组 & 干预措施
Standard FOLFIRI for wild/hetero UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Irinotecan Injection [Camptosar] (Drug)
Standard FOLFIRI for wild/hetero UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: 5-fluorouracil (Drug)
Standard FOLFIRI for wild/hetero UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Leucovorin (Drug)
Reduced Dose of CPT-11 for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 90 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Irinotecan Injection [Camptosar] (Drug)
Reduced Dose of CPT-11 for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 90 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: 5-fluorouracil (Drug)
Reduced Dose of CPT-11 for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 90 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Leucovorin (Drug)
Standard FOLFIRI for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Irinotecan Injection [Camptosar] (Drug)
Standard FOLFIRI for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: 5-fluorouracil (Drug)
Standard FOLFIRI for homo UGT1A1
Irinotecan Injection [Camptosar] (CPT-11) 180 mg/m2, day 1; Leucovorin (LV) 400mg/m2, day 1; 5-fluorouracil (5-FU) 400mg/m2, day 1, 5-fluorouracil (5-FU) 2400mg/m2, day 1; Repeat every two weeks.
干预措施: Leucovorin (Drug)
结局指标
主要结局
Incidence of toxicity, especially neutropenia and diarrhea
时间窗: From the beginning of treatment to the whole treatment period, an expected average of 6-8 months.
Association between UGT1A1 polymorphism, CPT-11 dosage and incidence of toxicity, especially neutropenia and diarrhea.
次要结局
- Response rate(Every 6 weeks, an expected average of 6-8 months.)
- Progression-free survival (PFS)(An expected average of 6-8 months.)
- Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.(The first treatment cycle.)
研究者
Xu jianming
Director of Department of GI Cancer
The Affiliated Hospital of the Chinese Academy of Military Medical Sciences