Fruquintinib (HMPL-013) is a novel oral small molecule that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts. Combined with hepatic arterial infusion chemotherapy (HAIC), this study is conducted to assess the efficacy and safety of this regimen in patients with unresectable colorectal cancer liver metastases as the third-line therapy.

This will be a single-arm, open-label, phase II study. This study will be divided into 2 stages: dose exploration and dose expansion. In the dose exploration stage, "3+3 dose escalation" design will be applied to determined the maximum tolerated dose (MTD) of fruquintinib for next stage:

Cohort A: HAIC + fruquintinib 3mg QD, 3 weeks on/1 week off (3w/1w). Cohort B: HAIC + fruquintinib 4mg QD, 3w/1w. Cohort C: HAIC + fruquintinib 5mg QD, 3w/1w.

All subjects of this study will be permitted to continue therapy with only safety monitoring and assessments for progression, if the product is well tolerated and the subject has stable disease or better.

Inclusion Criteria:

1. Male or female, age ≥ 18 years and ≤75, at the time of study entry.
2. Histologically or cytologically documented advanced colorectal carcinoma with unresectable liver metastasis (existence of extrahepatic metastasis is acceptable).
3. Previously received 2 lines of standard chemotherapy, including 5-FU, oxaliplatin, and irinotecan.
4. Subjects must have at least one measurable lesion per RECIST v1.1.
5. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
6. Estimated life expectancy of ≥12 weeks.
7. Adequate organ functions verified by laboratory tests within 7 days before the first intervention, including bone marrow, liver and kidney function, and coagulation function
8. Female subjects of childbearing potential who are sexually active with a nonsterilized male partner must use an acceptable method of contraception from screening, and must agree to continue using such precautions for 90 days after the final dose of investigational product.
9. Written and signed informed consent.

Exclusion Criteria:

1. ANC<1.5×10*9/L, PLT<80×10*9/L, or Hb<9g/dL; no blood infusion within 2 weeks.
2. TBil>2.5 × ULN.
3. AST or ALT>5 × ULN.
4. Serum Cr>1.5 × ULN, or CrCl<50 ml/min (calculated by Cockcroft-Gault equation)
5. APTT or PT> 1.5 × ULN.
6. Clinically significant electrolyte abnormalities determined by investigators.
7. Proteinuria ≥ 2+ (1.0g/24hr).
8. Hypertension that cannot be controlled by drugs, which is specified as: systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg
9. Active gastrointestinal ulceration, ulcerative colitis, or gastrointestinal bleeding; potential gastrointestinal bleeding or perforation determined by investigators.
10. History of arterial thrombosis or deep venous thrombosis within 6 months before enrollment; evidence of hemorrhagic tendency or receiving anticoagulant therapy within 2 months before enrollment.
11. Stroke or transient cerebral ischemia occurred within 12 months before enrollment.
12. History of cardiovascular disease within 6 months before enrollment, including congestive heart failure (NYHA grade>2), acute myocardial ischemia, severe/unstable angina or CABG; or LVEF<50%.
13. Uncontrollable malignant ascites, pleural effusion, or pericardial effusion (determined by investigators).
14. Previous treated with VEGFR inhibitors.
15. Other malignant tumors in the past 5 years, except skin basal cell or squamous cell carcinoma after radical surgery, or cervical carcinoma in situ.
16. Evidence of CNS metastasis.
17. Active infection, such as acute pneumonia, active stage of HBV/HCV.
18. Pregnant or lactating women.
19. By judgment of the investigator, there are concomitant diseases that seriously endanger the safety of the patient or affect the completion of the study.
20. Severe mental illness.