Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients
- Conditions
- Metastatic Colorectal Cancer
- Interventions
- Registration Number
- NCT01523431
- Lead Sponsor
- The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 583
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Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
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At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
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Aged 18 years or older
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ECOG performance status of ≤ 2.
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Anticipated life expectancy of ≥ 3 months.
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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).
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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
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Written informed consent can be obtained prior to their participation in the trial.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Standard FOLFIRI for wild/hetero UGT1A1 Irinotecan Injection [Camptosar] 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. Standard FOLFIRI for homo UGT1A1 Irinotecan Injection [Camptosar] 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. Reduced Dose of CPT-11 for homo UGT1A1 Irinotecan Injection [Camptosar] 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. Standard FOLFIRI for wild/hetero UGT1A1 5-fluorouracil 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. Standard FOLFIRI for wild/hetero UGT1A1 Leucovorin 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. Reduced Dose of CPT-11 for homo UGT1A1 5-fluorouracil 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. Standard FOLFIRI for homo UGT1A1 5-fluorouracil 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. Reduced Dose of CPT-11 for homo UGT1A1 Leucovorin 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. Standard FOLFIRI for homo UGT1A1 Leucovorin 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.
- Primary Outcome Measures
Name Time Method Incidence of toxicity, especially neutropenia and diarrhea 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.
- Secondary Outcome Measures
Name Time Method Response rate Every 6 weeks, an expected average of 6-8 months. Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response.
Progression-free survival (PFS) An expected average of 6-8 months. Association between UGT1A1 polymorphism, CPT-11 dosage and PFS. PFS is defined as the length of time from randomise to disease progression or to death from any cause other than progression.
Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. The first treatment cycle. Association between UGT1A1 polymorphism, CPT-11 dosage and pharmacokinetics of irinotecan. Plasma concentration of irinotecan and its metabolites, SN-38 and SN-38G are determined using high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS).
Trial Locations
- Locations (1)
Affiliated Hospital Cancer Center, Academy of Military Medical Sciences (307 Hospital of PLA)
🇨🇳Beijing, Beijing, China