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

• Association between UGT1A1 polymorphism and irinotecan pharmacokinetics [ Time Frame: First 3 days from the treatment beginning ] [ Designated as safety issue: No ]
  Determine human plasma concentrations of irinotecan and its metabolites, SN-38, SN-38G, using high-performance liquid chromatography with fluorescence detector (HPLC-FLD)
• Progression-free survival [ Time Frame: an expected average of 6 months ] [ Designated as safety issue: No ]
  PFS is defined as the length of time from randomise to disease progression of or to death from any cause other than progression.
• Response rate [ Time Frame: every 6 weeks,an expected average of 6 months ] [ Designated as safety issue: No ]
  According to RECIST criteria

The purpose of this study is to investigate the influence of dose selection of CPT-11 on pharmacokinetics, response and toxicity according to UGT1A1 genotype in colorectal cancer patients.

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 UGT1A1 *28 or UGT1A1 *6 genotype patients.

• Active Comparator: homozygous UGT1A1*1
  CPT-11(Irinotecan ) 180 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
  Intervention: Drug: CPT-11
• Active Comparator: UGT1A1*1/*28 or UGT1A1*1/*6
  CPT-11(Irinotecan ) 180 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
  Intervention: Drug: CPT-11
• Experimental: UGT1A1*28/*28 or*6/ *6 or *28/*6
  CPT-11(Irinotecan ) 90 mg/m2 90-minute i.v. infusion on day 1; leucovorin 400mg/m2 i.v. infusion on day 1 ; followed by 5-FU 400mg/m2 i.v. bolus on day 1, then 2400mg/m2 i.v. over 46 hours continuous infusion; repeat every two weeks.
  Intervention: Drug: CPT-11

Inclusion Criteria:

1. Histologically confirmed colorectal cancer patients who received no prior chemotherapy or failed to 1st line treatments
2. At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
3. Aged 18 years or older
4. ECOG performance status of ≤ 2.
5. Anticipated life expectancy of ≥ 3 months.
6. 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).

7. 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
8. Written informed consent can be obtained prior to their participation in the trial.

Exclusion Criteria:

1. Pregnant or breast feeding women
2. Subjects who have previously received CPT-11 treatment
3. Serious concurrent complication, severe active infection.
4. Subjects with chronic diarrhea, acute or sub acute Intestinal obstruction.
5. Subjects with uncontrolled CNS metastasis or epilepsia or severe psychiatric disorders.
6. Subjects who are regarded to be unsuitable for this trial by the investigator.
7. Subjects who are participating in other clinical trials