Pemetrexed and TAS-102 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* Subjects who have withdrawn from standard treatment due to unacceptable toxicity and precluding retreatment with the same agent prior to progression of disease will also be allowed.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 0-2.
* 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 TAS-102, 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.