Individual Dosage Selection of Irinotecan (CPT-11) Based on UGT1A1 Genotype in Metastatic Colorectal Cancer Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Irinotecan Injection [Camptosar]
* Drug: 5-fluorouracil
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ≤ 2. 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard FOLFIRI for wild/hetero UGT1A1<br>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. | Drug: Irinotecan Injection [Camptosar]<br>* CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.<br>* Other names: FOLFIRI regimen;Drug: 5-fluorouracil<br>* The 5-FU dosage will remain the standard.<br>* Other names: FOLFIRI regimen;Drug: Leucovorin<br>* The LV dosage will remain the standard.<br>* Other names: FOLFIRI regimen;|
| Experimental: Reduced Dose of CPT-11 for homo UGT1A1<br>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. | Drug: Irinotecan Injection [Camptosar]<br>* CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.<br>* Other names: FOLFIRI regimen;Drug: 5-fluorouracil<br>* The 5-FU dosage will remain the standard.<br>* Other names: FOLFIRI regimen;Drug: Leucovorin<br>* The LV dosage will remain the standard.<br>* Other names: FOLFIRI regimen;|
| Active Comparator: Standard FOLFIRI for homo UGT1A1<br>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. | Drug: Irinotecan Injection [Camptosar]<br>* CPT-11 will be administered according to UGT1A1 genotypes. Patients with UGT1A1 *1/*1 or heterozygous UGT1A1*1/*28 or *1/*6 will receive standard dose of CPT-11. Patients with homozygous UGT1A1*28/*28, *6/*6 or *28/*6, will be randomized in a 1:1 ratio to receive standard dose of CPT-11 or 50% reduced dose of CPT-11.<br>* Other names: FOLFIRI regimen;Drug: 5-fluorouracil<br>* The 5-FU dosage will remain the standard.<br>* Other names: FOLFIRI regimen;Drug: Leucovorin<br>* The LV dosage will remain the standard.<br>* Other names: FOLFIRI regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity, especially neutropenia and diarrhea | Association between UGT1A1 polymorphism, CPT-11 dosage and incidence of toxicity, especially neutropenia and diarrhea. | From the beginning of treatment to the whole treatment period, an expected average of 6-8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Association between UGT1A1 polymorphism, CPT-11 dosage and tumor response. | Every 6 weeks, an expected average of 6-8 months. | 
| Progression-free survival (PFS) | 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. | An expected average of 6-8 months. | 
| Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G. | 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). | The first treatment cycle. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Irinotecan, UGT1A1 genotype, Neutropenia, diarrhea, response, pharmacokinetic