Patients with advanced colorectal cancer, particularly those of the pMMR/MSS type, exhibit suboptimal therapeutic responses in the third-line and subsequent treatments. The efficacy of the existing standard treatment regimens is highly restricted. In the CORRECT study, the median overall survival (OS) of regorafenib was 6.4 months, the median progression-free survival (PFS) was 1.9 months, and the objective response rate (ORR) was 1%. In the CONCUR study targeting the Asian population, the median OS of the regorafenib group was 8.8 months, the median PFS was 3.2 months, and the ORR was 4%. In the FRESCO study, the median OS of fruquintinib was 9.3 months, the median PFS was 3.7 months, and the ORR was 4.7%. In the TERRA study, the median OS of trifluridine/tipiracil (TAS-102) was 7.8 months, the median PFS was 2.0 months, and the ORR was 1.1%. The SUNLIGHT study explored the combined treatment modality of TAS-102 plus bevacizumab, where the median OS of the combined regimen was 10.8 months, the median PFS was 5.6 months, and the ORR was 6.1%. Evidently, the therapeutic efficacy of advanced colorectal cancer in the third-line and beyond has plateaued. In recent years, fundamental research has discovered that epigenetic regulation significantly synergizes with anti-angiogenesis and immune checkpoint inhibition therapy. Small-scale clinical explorations have also indicated favorable efficacy and clinical prospects, warranting further investigation. Hence, we contemplate employing the combination of chidamide, regorafenib, and iparomlimab/tuvonralimab to investigate its efficacy and safety in the treatment of advanced colorectal cancer in the third-line and beyond, and to explore novel breakthroughs for refractory colorectal cancer after multiple lines of treatment.

The aim of this study is to assess the efficacy and safety of the combination regimen of chidamide, regorafenib, and iparomlimab/tuvonralimab in patients with advanced colorectal cancer in the third-line and beyond. The study will be conducted at Shanghai Changzheng Hospital. The study drugs, including chidamide, regorafenib, and iparomlimab/tuvonralimab, are all commercially available in China.

Inclusion Criteria:

• Patients with advanced colorectal adenocarcinoma confirmed by histology or cytology;
• Those who have experienced disease progression or are intolerant to treatment after receiving ≥ 2 lines of systemic standard therapy;
• Patients must have at least one measurable lesion (according to RECIST 1.1 criteria);
• Patients who have received local radiotherapy at least 3 weeks before the first drug treatment are eligible for inclusion; however, the lesions evaluated by RECIST must not be within the radiotherapy field;
• Patients must be at least 18 years old;
• Performance status ECOG score of 0-1;
• Expected survival ≥ 12 weeks;
• Patients must have the ability to understand and voluntarily sign the written informed consent form;
• Women of childbearing age must have a negative pregnancy test within 7 days before the start of treatment. During the study period, both the patient and the patient's spouse must take contraceptive measures.

Exclusion Criteria:

• Patients who have undergone major surgery or suffered severe trauma within 4 weeks prior to the first dose of the study drug;
• Patients with hypersensitivity to any component of the study protocol;
• Patients planning to conceive or who are pregnant;
• Patients with brain metastases and an inability to accurately describe their condition;
• Patients who have experienced any of the following diseases within 6 months prior to the start of the study treatment: myocardial infarction, severe/unstable angina pectoris, NYHA class 2 or higher congestive heart failure, uncontrolled arrhythmia, etc.;
• Abnormal laboratory tests:

Absolute neutrophil count (ANC) < 1,500/mm3; Platelet count < 75,000/mm3; Total bilirubin > 1.5 times the upper limit of normal; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 times the upper limit of normal (for patients with liver metastases > 5 times the upper limit of normal); Creatinine > 1.5 times the upper limit of normal;

• Patients who have had other cancers (except advanced colorectal cancer) within 5 years prior to the start of this study treatment. Cervical carcinoma in situ, cured basal cell carcinoma and bladder epithelial tumors are excluded;
• Patients with a history of drug abuse, drug addiction, or alcohol dependence;
• Patients without legal capacity or with limited civil capacity;
• Other conditions that the investigator deems inappropriate for inclusion in the study.