This phase II study aims to explore the efficacy and safety of fruquintinib combined with TAS-102 in the third-line treatment of patients with advanced metastatic colorectal cancer.

This is a prospective, single center, one-arm phase II study. A total of 54 advanced mCRC patients refractory to standard therapies will be enrolled and administered with fruquintinib (4mg/d, qd po, D1-21, Q4W) combined with TAS-102 (70mg/m2/d, bid po, D1-5, 8-12, Q4W) until intolerable toxicity, disease progression or death. Primary endpoint of this study is PFS and secondary endpoints are OS, ORR, DCR and safety.

Inclusion Criteria:

1. ≥ 18 and ≤ 75 years of age;
2. Histological or cytological confirmed advanced metastatic colorectal cancer;
3. Refractory to at least second line standard treatment containing fluorouracil, oxaliplatin and irinotecan;
4. At least one measurable lesion (larger than 10 mm in diameter by spiral CT scan or 20mm by conventional CT scan);
5. ECOG performance status of 0-1;
6. Life expectancy ≥ 12 weeks;
7. No previous treatment with vascular endothelial growth factor receptor (VEGFR) inhibitor (TKI);
8. Signed and dated informed consent;
9. Adequate hepatic, renal, heart, and hematologic functions;
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure.

Exclusion Criteria:

1. Pregnant or lactating women;
2. Any factors that influence the usage of oral administration or any disease or condition that affects drug absorption;
3. Previous treatment with TAS-102;
4. Participated in clinical trials of other drugs within four weeks before enrollment;
5. Received other systemic anti-tumor therapy within 4 weeks before enrollment, including chemotherapy, signal transduction inhibitors, hormone therapy and immunotherapy;
6. International normalized ratio (INR) > 1.5 or partially activated prothrombin time (APTT) > 1.5 × ULN;
7. Clinically significant electrolyte abnormalities;
8. Subjected with hypertension that cannot be controlled by drugs, which is specified as: systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg;
9. Unrelieved toxic reactions higher than CTCAE V5.0 grade 1 caused by any previous anti-cancer treatment;
10. Incomplete healing of skin wound, surgical site, traumatic site, severe mucosal ulcer or fracture;
11. Conditions that may cause gastrointestinal bleeding and perforation determined by the researcher;
12. History of arterial thrombosis or deep venous thrombosis within 6 months before enrollment;
13. Stroke and / or transient cerebral ischemia occurred within 12 months before enrollment;
14. Cardiovascular diseases with significant clinical significance;
15. LVEF<50%;
16. Congestive heart failure New York Heart Association (NYHA) grade > 2;
17. Evidence of CNS metastasis;
18. Previous treatment with VEGFR inhibition;
19. Ventricular arrhythmias requiring drug treatment;
20. Proteinuria ≥ 2+ (1.0g/24hr);
21. Coagulation dysfunction, hemorrhagic tendency or receiving anticoagulant therapy;
22. Other malignant tumors in the past 5 years, except skin basal cell or squamous cell carcinoma after radical surgery, or cervical carcinoma in situ;
23. Active infection that is not controlled clinically, such as acute pneumonia, active hepatitis B or hepatitis C;
24. By judgment of the investigator, there are concomitant diseases that seriously endanger the safety of the patient or affect the completion of the study.