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

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

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.

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:

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.