Patients will be treated with irinotecan (150 mg/m2) followed by oxaliplatin (85 mg/m2) on day 1 and S-1 (80 mg/m2/day) from day 1 to 14 every 3 weeks. Patients will receive up to a planned treatment of maximum 12 cycles of chemotherapy. Response assessment will be performed every 2 cycles of chemotherapy.

Inclusion Criteria:

• Histologically confirmed unresectable or metastatic colorectal cancer, not amenable to surgery or radiation treatment for curative intent
• At least one unidimensional measurable lesion
• ECOG performance status 0-2.
• No prior chemotherapy in metastatic settings, but adjuvant or neo-adjuvant treatment for non-metastatic (M0) disease is allowed if completed at least 6 months prior to initiation of study treatment
• Adequate major organ functions
• Give written informed consent

Exclusion Criteria:

• Prior systemic chemotherapy for metastatic disease
• Prior treatment with oxaliplatin or irinotecan
• Prior radiotherapy is permitted if it was not administered to target lesions selected for this study and provided it has been completed at least 4 weeks before registration
• Prior surgical treatment of stage IV disease is permitted
• CNS metastases
• Prior history of peripheral neuropathy ≥ NCI CTC grade 1
• Uncontrolled or severe cardiovascular disease
• Serious concurrent infection or nonmalignant illness
• Other malignancy within the past 3 years except cured non-melanomatous skin cancer or carcinoma in situ of the cervix
• Organ allografts requiring immunosuppressive therapy
• Psychiatric disorder or uncontrolled seizure that would preclude compliance
• Pregnant, nursing women or patients with reproductive potential without contraception
• Patients receiving a concomitant treatment with drugs interacting with S-1 such as flucytosine, phenytoin, or warfarin et al.
• Prior unanticipated severe reaction to fluoropyrimidine therapy, or known dihydropyrimidine dehydrogenase (DPD) deficiency
• Known hypersensitivity to platinum compounds or any of the components of the study medications
• Major surgery within 3 weeks prior to study treatment starts, or lack of complete recovery from the effects of major surgery
• Received any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment with study drug