Comparing Chidamide+Sintilimab+Bev With Standard Second-line FOLFIRI+Bev in Advanced MSS/pMMR mCRC

Inclusion Criteria:

1. Locally advanced unresectable or metastatic colorectal adenocarcinoma (excluding mixedadenosquamous carcinoma and other pathological types) confirmed by pathologicalhistology or cytology.
2. Diagnosis of pMMR confirmed by PCR for microsatellite stability (MSS) or lowmicrosatellite instability (MSI-L), or by immunohistochemistry for DNA mismatch repair (MMR) proteins, including MLH1, MSH2, MSH6 and PMS2 protein expression, which resultin no protein deletion.
3. Patients who have failed first-line oxaliplatin-containing standard therapy and haveimaging evidence (e.g., CT scan) or clinical evidence (e.g., cytology report of newascites or pleural effusion) of disease progression during or after treatment;patients whose intolerance of toxicity has led to discontinuation of first-lineoxaliplatin-containing standard therapy may be enrolled; relapse within 180 days afterthe last dose of oxaliplatin-containing adjuvant therapy.
4. There is at least one measurable lesion according to RECIST v1.1.
5. ECOG PS score is in the range of 0~1.
6. Subjects who have signed a written informed consent form and who are able to complywith the visits and related procedures specified in the protocol.
7. Aged ≥ 18 years old and ≤ 75 years old.
8. Expected survival time ≥ 18 weeks.
9. Female subjects of childbearing age or male subjects whose sexual partners are atchildbearing age are required to take effective contraception measures throughout thetreatment period and for 6 months after the treatment (see section 4.3 of theprotocol).
10. Subjects having adequate organ and bone marrow functions with laboratory test valueswithin 7 days prior to enrollment meeting the following requirements (no bloodcomponents, cell growth factors, albumin, and other corrective therapy drugs areallowed to be given within the first 14 days of obtaining laboratory tests), asfollows:

1. Blood routine: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count (PLT) ≥ 100×109/L; hemoglobin level (HGB) ≥ 9.0 g/dL.
2. Liver function: serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN);alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN in subjectswithout liver metastases, and ALT and AST ≤ 5.0 × ULN in subjects with liver metastases;serum albumin ≥ 25 g/L.
3. Renal function: serum creatinine (Cr) ≤ 1.5 x ULN. 4) Patients with routine urineresults showing urine protein <2+ or routine urine testing showing urine protein ≥ 2+ atbaseline should undergo 24-hour urine collection and 24-hour urine protein quantification < 1 g.
4. Coagulation function: international normalized ratio (INR) ≤ 1.5×ULN and activatedpartial thromboplastin time (APTT) ≤ 1.5×ULN.

Exclusion Criteria:

1. Prior exposure to any anti-PD-1 antibody, anti-PD-L1 antibody, HDAC inhibitor, oririnotecan.
2. Receiving any investigational drug within 4 weeks prior to the first dose of the studydrug.
3. Concurrent participation in another interventional clinical study, except in anobservational (non-interventional) clinical study or in the follow-up phase of aninterventional study.
4. Receiving the last dose of antitumor therapy (chemotherapy, targeted therapy, tumorimmunotherapy, or tumor embolization) within 3 weeks prior to the first dose.
5. Receiving radiotherapy within 4 weeks prior to the first dose.
6. Patients who have received radiotherapy more than 4 weeks prior to the first dose withany radiotherapy-related toxic reactions, such as radiation pneumonia, radiationhepatitis, radiation enteritis, including clinical symptoms only, or requiringglucocorticoid therapy.
7. Use of immunosuppressive drugs within 4 weeks prior to the first dose, excludingtopical glucocorticoids by nasal spray, inhalation or other routes or physiologicaldoses of systemic glucocorticoids (i.e., no more than 10 mg/day prednisone orequivalent doses of other glucocorticoids).
8. Receiving live attenuated vaccine within 4 weeks prior to the first dose or planningto receive during the study period.
9. Major surgical procedure (craniotomy, thoracotomy or open heart surgery) or unhealedwound, ulcer or fracture within 4 weeks prior to the first dose.
10. Presence of toxicity (excluding alopecia, non-clinically significant and asymptomaticlaboratory abnormalities) from prior antineoplastic therapy not recovered to ≤ grade 1by NCI common terminology criteriafor adverse events (CTCAE) Version 5.0 (NCI CTCAEVersion 5.0) prior to the first dose.
11. Known presence of symptomatic CNS metastases and/or carcinomatous meningitis. Subjectswith prior treatment for brain metastases may participate in the study provided thatthe brain metastases have remained stable for at least 4 weeks prior to the first doseof study treatment; and that neurological symptoms have recovered to ≤ grade 1 by NCICTCAE version 5.0.
12. Active autoimmune disease requiring systemic therapy (e.g., use of disease-relievingdrugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose.Alternative therapies (e.g., thyroxine, insulin, or physiologic corticosteroids foradrenal or pituitary insufficiency) are allowed. A known history of primaryimmunodeficiency. For patients with only positive autoimmune antibodies, the presenceof autoimmune diseases should be confirmed at the discretion of the investigator.
13. Patients who are known to have active tuberculosis and are receiving anti-tuberculosistreatment or have received anti-tuberculosis treatment within 1 year prior to thefirst dose.
14. Known to have interstitial lung disease requiring steroid hormone therapy.
15. Known to have acute or chronic active hepatitis B (HBsAg positive and HBV DNA ≥ 200IU/mL or ≥ 103 copies/mL) or acute or chronic active hepatitis C (HCV antibodypositive and HCV RNA positive).
16. Infected with human immunodeficiency virus (HIV) (HIV 1/2 antibody positive), known tobe infected with syphilis.
17. Severe infections that are in the active phase or poorly controlled in clinicalpractice. Serious infection, including but not limited to hospitalization forcomplications of infection, bacteremia or severe pneumonia, within 4 weeks prior tothe first dose.
18. Significant malnutrition, such as the need for intravenous supplemental nutrientsolutions; except for malnutrition corrected more than 4 weeks prior to the firstdose.
19. Symptomatic congestive heart failure (New York Heart Association class II-IV);symptomatic or poorly controlled arrhythmias.
20. Uncontrolled arterial hypertension (systolic blood pressure ≥ 150 mmHg or diastolicblood pressure ≥ 100 mmHg) even with standard treatment.
21. Any arterial thromboembolic event including myocardial infarction, pulmonary embolism,and unstable angina within 6 months prior to enrollment.
22. A history of deep vein thrombosis or any other serious thromboembolism (implantable IVport or catheter-derived thrombosis, or superficial vein thrombosis is not considered "serious" thromboembolism) within 3 months prior to enrollment.
23. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or more severecirrhosis.
24. A history of gastrointestinal perforation and/or fistula in the previous 6 months; ahistory of peptic ulcer, a history of intestinal obstruction (including incompleteintestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection complicated by chronicdiarrhea), Crohn's disease, ulcerative colitis, abdominal abscess, or long-termchronic diarrhea. Post-intestinal stent implantation.
25. > 3 loose stools per day at baseline, suggesting a predisposition to colon or smallbowel disease with uncontrollable symptoms.
26. A history of allergy or known intolerance to atropine sulfate or loperamide or theappropriate antiemetic in combination with FOLFIRI.
27. Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases orsecondary reactions to cancer and can lead to higher medical risk and/or uncertaintyin survival evaluation.
28. A known history of inherited bleeding tendency disorders or coagulation disorders
29. Any life-threatening bleeding event within the previous 3 months, including the needfor blood transfusion therapy, surgical or local treatment, or ongoing drug therapy.
30. A high risk of bleeding as determined by the investigators: cirrhosis with severeesophagogastric fundic varices, intermittent or persistent non-fatal bleeding events (including but not limited to intermittent bloody stools or positive occult blood dueto primary intestinal lesions, intermittent hemoptysis due to pulmonary metastases).
31. Cerebrovascular accident (including transient ischemic attack) in the previous 6months.
32. Use of aspirin (>325 mg/day) or other NSAIDs known to inhibit platelet function for 10consecutive days within 10 days prior to the first dose.
33. Treatment with oral or parenteral anticoagulants or thrombolytics for 10 consecutivedays within 10 days prior to the first dose. However, prophylactic use ofanticoagulants is allowed.
34. Pleural fluid, ascites, and pericardial effusion with clinical symptoms or requiringdrainage, except for small amounts of pleural fluid, small amounts of ascites, andsmall amounts of pericardial effusion without clinical symptoms on imaging only.
35. A history of other primary malignancies, except: malignancies in complete response forat least 2 years prior to enrollment and requiring no other treatment during the studyperiod; adequately treated non-melanoma skin cancer or malignant freckled nevus withno evidence of disease recurrence; adequately treated carcinoma in situ with noevidence of disease recurrence.
36. A known history of allogeneic organ transplantation and allogeneic hematopoietic stemcell transplantation.
37. Known to be allergic to any monoclonal antibody component.
38. Female subjects in the pregnancy or lactating period.
39. A history of alcohol or drug abuse.
40. Other acute or chronic illnesses, psychiatric disorders, or abnormal laboratory testvalues that may result in the following outcomes: increasing the risk associated withstudy participation or study drug administration, or interfering with theinterpretation of study results and, at the investigator's discretion, classifying thepatient as ineligible for participation in this study.