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

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.