Pemetrexed and S-1 in Combination With Bevacizumab in Refractory Colorectal Cancer

Inclusion Criteria: * Histological or cytological documentation of adenocarcinoma of the colon or rectum. All other histological types are excluded. * Subjects with metastatic colorectal cancer(CRC) (Stage IV). * Subjects must have failed at least two lines of prior treatment, which must include a fluoropyrimidine, oxaliplatin and irinotecan. * Subjects have failed or refused third-line treatment with regorafenib or fruquintinib. * Subjects treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy. * Subjects who have withdrawn from standard treatment due to unacceptable toxicity and precluding retreatment with the same agent prior to progression of disease will also be allowed. * Prior treatment with bevacizumab and/or cetuximab will be allowed, but the use of bevacizumab should be no more than one single line treatment. * Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1.is necessary. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. * Life expectancy of at least 3 months. * Adequate bone marrow, liver, cardiac and renal function as assessed by the laboratory required by protocol. * Assigned informed consent. Exclusion Criteria: * Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\]. * Participants of other clinical trial within 4 weeks. * Diseases which will impact the absorption of S-1, eg. dysphagia, chronic diarrhea, bowl obstruction * Hemorrhage events of ≥grade 3 within 4 weeks. * Known central nervous system metastasis. * Uncontrolled hypertension. (Systolic blood pressure 140 mmHg or diastolic pressure 90 mmHg despite optimal medical management). Unstable angina,congestive heart failure,Myocardial infarction, Cardiac arrhythmias requiring anti-arrhythmic therapy. * Urine protein ≥++ and 24h urine protein more than 1.0g. * Chronically green wound or bone fracture. * Arterial or venous thrombotic or embolic events. * Tumor invading important blood vessel with high risk of severe hemorrhage. * Current active bleeding or any surgery taken within 2 months. * Abnormal coagulation function. * Thromboemboli events within 6 months. * Immune diseases or organ transplantation history.