A randomised, open-label, multicenter phase III study to evaluate the efficacy and safety of tucidinostat in combination with sintilimab and bevacizumab versus fruquintinib monotherapy in MSS/pMMR colorectal cancer patients.

This is a randomised, open-label, multicenter phase III study evaluating the efficacy and safety of tucidinostat in combination with sintilimab and bevacizumab versus fruquintinib monotherapy in MSS/pMMR colorectal cancer patients. 430 patients will be randomised (1:1) to receive tucidinostat in combination with sintilimab and bevacizumab (experimental arm) or fruquintinib monotherapy (control arm).

Inclusion Criteria:

1. Provide written informed consent for the study.
2. Age ≥18 years and ≤75 years.
3. Histologically or cytologically confirmed unresectable and metastatic colorectal adenocarcinoma.
4. Has been previously treated and has shown disease progression or could not tolerate standard treatment, which must include fluoropyrimidine, irinotecan and oxaliplatin, with or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) .
5. Have confirmed MSS or MSI-L, or pMMR.
6. KRAS status must have been previously determined (mutant or wild-type) .
7. Measurable disease per RECIST v1.1.
8. ECOG PS 0 or 1.
9. Adequate organ function.
10. Expected survival >12 weeks.

Exclusion Criteria:

1. Prior use of HDAC inhibitor.
2. Received prior therapies targeting PD-1, PD-L1, CTLA4, or any other immune checkpoint pathway.
3. Prior use of small-molecule tyrosine kinase inhibitor of VEGF receptors.
4. Received any anti-tumor therapy or investigational agent and device within 28 days before the first dose of study treatment.
5. Received radiotherapy within 28 days before the first dose of study treatment.
6. If randomized into the control group, it is planned to use the combination of tucidinostat with PD-1 inhibitor and bevacizumab after the end of study treatment.
7. History of autoimmune diseases requiring systemic treatment within 2 years before the first dose of study treatment.
8. Known history of primary immunodeficiency.
9. Received systemic immunosuppressive drugs within 28 days before the first dose of study treatment.
10. Received systemic immunostimulatory drugs within 28 days before the first dose of study treatment.
11. Received major surgery within 28 days before the first dose of study treatment.
12. Received a live vaccine within 28 days before the first dose of study treatment or planned to receive during the study period.
13. Has not recovered ( ≤ Grade 1 defined by CTCAE V5.0) from AEs due to prior anti-cancer therapy.
14. Has uncontrolled diabetes assessed by investigators within 7 days before the first dose of study treatment.
15. Has symptomatic and untreated central nervous system (CNS) metastases.
16. Has uncontrollable or major cardiovascular disease.
17. History of cerebrovascular accidents within 6 months before the first dose of study treatment.
18. History of serious thromboembolism within 6 months before the first dose of study treatment.
19. History of gastrointestinal perforation and/or fistula etc., within 6 months before the first dose of study treatment.
20. Obvious gastrointestinal abnormalities during the screening period,which may affect the intake, transport or absorption of drugs.
21. Known history of bleeding disorders or coagulopathy.
22. Anticoagulants or thrombolytic agents are being used during the screening period.
23. Uncontrolled pleural/abdominal/pericardial effusion that was drained within 14 days before the first dose of study treatment.
24. Suspected interstitial lung disease (ILD) or pulmonary fibrosis or pulmonary inflammation requiring treatment.
25. Severe or active infection requiring systemic therapy.
26. Known active pulmonary tuberculosis.
27. Active hepatitis B or hepatitis C.
28. HIV positive or syphilis infection.
29. History of malignant tumor.
30. History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
31. History of hypersensitivity to study drugs, or any of its excipients.
32. History of alcohol or drug abuse.
33. Unwilling or unable to comply with procedures required in this protocol.
34. Pregnant or breast-feeding women. Male/Female is unwilling or unable to use a highly effective method of birth control.
35. Any condition not suitable for participating in the trial in the opinion of the Investigator.