A Study of Tucidinostat in Combination With Sintilimab and Bevacizumab 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

• Provide written informed consent for the study.
• Age ≥18 years and ≤75 years.
• Histologically or cytologically confirmed unresectable and metastatic colorectal adenocarcinoma.
• 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) .
• Have confirmed MSS or MSI-L, or pMMR.
• KRAS status must have been previously determined (mutant or wild-type) .
• Measurable disease per RECIST v1.1.
• ECOG PS 0 or 1.
• Adequate organ function.
• Expected survival >12 weeks.

Exclusion criteria

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