A Genotype-guided Study of Irinotecan Administered in Combination With 5-fluorouracil/Leucovorin (FOLFIRI) and Bevacizumab in Advanced Colorectal Cancer Patients

Inclusion criteria

• Histologically or cytologically confirmed diagnosis of metastatic colorectal adenocarcinoma
• No prior chemotherapy for metastatic disease
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (5. Life expectancy > 3 months
• Adequate organ function, including bone marrow (absolute neutrophil count (ANC) ≥l500/μl, haemoglobin ≥ 9g/dL, platelets ≥ 100,000/ μl); hepatic (total bilirubin < 1.6 mg/dl;SGOT and SGPT < 2.5 x upper limit of normal for patients without liver metastases and < 5x upper limit of normal for patients with liver metastases); and renal (serum creatinine ≤ 1.5x upper limit of normal).
• Patients who are eligible to be registered in the study, based upon the above criteria, will be genotyped for the UGT1A1*28 polymorphism and stratified into two groups based on the presence of the UGT1A1*1/*1 or UGT1A1*1/*28 genotype.
• Patients with the UGT1A1*28/*28 genotype or carriers of the other alleles (TA5 and TA8)will be excluded.
• For patients to be evaluable for response (a secondary end point), they must have at least one measurable lesion as defined by RECIST (i.e., lesions that can be accurately measured in at least one dimension with the longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm using spiral CT scan).
• Patients without measurable lesions can be included and will be evaluated only for toxicity.
• Signed informed consent and local IRB approval is required.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, up until 30 days after final study treatment. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion criteria

• Prior irinotecan or bevacizumab treatment
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
• Diarrhea greater than grade 1
• Bowel obstruction
• Documented brain metastases
• Serious active infectious disease
• Active uncontrolled bleeding or fistulas
• Pregnancy
• Radiotherapy or major surgery within 4 weeks
• Previous or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or any other cancer for which the patient has been disease-free for five years.