The prognosis of most patients with unresectable locally advanced or metastatic colorectal cancer (CRC) remains poor despite the advancements in chemotherapy and target therapy.

CAPability-01 trial investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer.

Based on the previous findings of CAPability-01, we will further evaluate the efficacy and safety of sintilimab and chidamide in combination with fruquintinib in the same setting.

Inclusion Criteria:

1. Fully understand this study and voluntarily sign the informed consent form;

2. Age between 18-75 years inclusive;

3. Patients with histologically confirmed unresectable locally advanced, recurrent, or metastatic colorectal adenocarcinoma;

4. Failure of standard second-line systemic treatment with measurable lesions;

5. Tumor tissue tested for microsatellite stability (MSS) or low microsatellite instability (MSI-L) by PCR, or confirmed pMMR by immunohistochemistry for DNA mismatch repair (MMR) protein (including MLH1, MSH2, MSH6, and PMS2 protein expression);

6. ECOG performance status of 0-2, with no deterioration within 7 days;

7. BMI≥18;

8. Expected survival ≥3 months;

9. Major organ functions meet the following requirements (no use of any blood components and growth factors within 14 days before enrollment):

   • Absolute neutrophil count ≥1.5×109/L, white blood cells ≥4.0×109/L;
   • Platelets ≥100×109/L;
   • Hemoglobin ≥90g/L;
   • Total bilirubin TBIL ≤1.5 times ULN;
   • ALT and AST ≤5 times ULN;
   • Urea/BUN and creatinine (Cr) ≤1.5×ULN (and creatinine clearance (CCr) ≥ 50mL/min);
   • Left ventricular ejection fraction (LVEF) ≥50%;
   • Corrected QT interval by Fridericia's formula (QTcF) <470 milliseconds.
   • INR ≤1.5×ULN, APTT ≤1.5×ULN.

10. Women of childbearing age must use effective contraception;

11. Good compliance and cooperation with follow-up.

Exclusion Criteria:

1. Unable to comply with the study protocol or procedures;
2. Pregnant or breastfeeding women;
3. Concurrent with any of the following conditions: uncontrolled hypertension, coronary artery disease, arrhythmias, and heart failure;
4. Previous treatment with small molecule tyrosine kinase inhibitors for metastatic disease;
5. Previous treatment with romidepsin;
6. Previous treatment with immune checkpoint inhibitors for metastatic disease;
7. Uncontrollable severe concurrent infections;
8. Acute myocardial infarction, acute coronary syndrome, or CABG within 3 months before the first treatment;
9. Subjects allergic to the study medication or any of its excipients;
10. Known human immunodeficiency virus (HIV) infection. Known clinically significant liver disease history, including viral hepatitis [known carriers of hepatitis B virus (HBV) must exclude active HBV infection, i.e., HBV DNA positive (>1×10^4 copies/mL or >2000 IU/mL); known hepatitis C virus (HCV) infection and HCV RNA positive (>1×10^3 copies/mL)];

12. Patients whom the investigator deems inappropriate for inclusion in this study.