SBRT Sequential CapeOX Regimen Combined With Bevacizumab and Sintilimab in First-line Treatment of mCRC

Inclusion Criteria:

1. Provision of written Informed Consent Form (ICF) prior to any study specificprocedures;
2. Age ≥ 18 years, ≤75 years;
3. Histologically or cytologically confirmed advanced Stage IV primary colorectalcancer,metastases cannot be removed;
4. No prior systemic treatment for advanced or metastatic colorectal cancer (includingchemical therapy, epidermal growth factor receptor inhibitors such as cetuximab orpanizumab, vascular endothelial growth factor inhibitors such as bevacizumab, immunecheckpoint inhibitors such as anti-PD-1 or PD-L1 antibodies and anti-CTLA-4antibodies);
5. The interval between adjuvant or neoadjuvant chemotherapy is more than one year;
6. According to the definition of RECIST 1.1, the investigator determined that thepatient had at least one measurable disease;
7. At least one lesion is suitable for SBRT according to the evaluation of theresearchers;
8. Patients with brain metastasis who are asymptomatic or stable after local treatmentare allowed to be enrolled as long as they meet the following conditions:

1. Measurable lesions outside the central nervous system; 2) No central nervous systemsymptoms or no exacerbation of symptoms for at least 2 weeks; 3) no glucocorticoidtreatment or discontinuation of glucocorticoid treatment within 7 days prior toadministration of the first study drug;

9.ECOG 0-1; 10. Life expectancy >3 months; 11. LVEF ≥50%;

12.Adequate organ function, subject will meet the following laboratory criteria:

1. Absolute value of neutrophil (ANC) ≥1.5x109/L.
2. Platelet ≥90×109/L.
3. Hemoglobin≥ 9 g/dL.
4. Total bilirubin ≤1.5× upper normal value (ULN); Or total bilirubin & GT; ULN butdirect bilirubin ≤ ULN;
5. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or AST ≤5×ULN in patients with liver metastasis);
6. Serum creatinine ≤1.5×ULN and creatinine clearance rate (calculated by Cockcroft-Gaultformula) ≥60 mL /min;
7. Good coagulation function, defined as international standardized ratio (INR) orprothrombin time (PT) ≤1.5 ULN;
8. Normal thyroid function, defined as thyroid stimulating hormone (TSH) within thenormal range. If the baseline TSH is outside the normal range, subjects with total T3 (or FT3) and FT4 within the normal range may be enrolled;
9. Urinary protein <2 +; If urine protein ≥2+, the 24-hour urine protein quantificationmust be ≤1g.

13.Women of childbearing age must be willing to use adequate contraception during studydrug therapy.

Exclusion Criteria:

1. Prior treatment with anti-PD-L1, anti-PD-L2 drugs, or drugs that target anotherstimulating or co-inhibiting T-cell receptor (e.g., CTLA-4, OX-40, CD137);
2. Symptomatic or high-risk obstruction, bleeding, perforation, pneumonia (includingnoninfectious pneumonia with prior hormone therapy and pneumonia patients undertreatment), etc;
3. Other malignant diseases other than colorectal cancer were diagnosed within 5 yearsprior to first administration (excluding radical basal cell carcinoma of the skin,squamous carcinoma of the skin, and/or radical resected carcinoma in situ);
4. Subject is currently participating in an interventional clinical study or has beentreated with another study drug or study device in the 4 weeks prior to initialdosing;
5. An active autoimmune disease requiring systemic therapy (e.g., palliative drugs,glucocorticoids, or immunosuppressants) has occurred within 2 years prior to firstdosing. Alternative therapies (e.g. thyroxine, insulin, or physiologic glucocorticoidsfor adrenal or pituitary dysfunction) are not considered systemic;
6. Subjects were receiving systemic glucocorticoid therapy (excluding nasal spray,inhalation, or other topical glucocorticoid) or any other form of immunosuppressivetherapy within 7 days prior to study initial dosing;
7. Active hemoptysis (cough up at least 2.5ml or 1/2 teaspoon blood at a time) within 3months prior to administration of the drug in the first study;
8. Imaging shows tumor invasion/invasion of large vessels or bleeding tendency asassessed by investigator or radiologist;
9. Had major surgery within 4 weeks prior to administration of the first study drug (except for surgery for biopsy purposes) or expected to have major surgery during thestudy period;
10. Severe unhealed wounds, ulcers or fractures;
11. Current or recent use of aspirin (within 10 days prior to receiving the first studydose) for 10 consecutive days (> 325 mg/ day) or other non-steroidal anti-inflammatorydrugs known to inhibit platelet function; Current or recent (within 10 days prior toreceiving the first study dose) treatment with a full-dose oral or parenteralanticoagulant or thrombolysis agent for 10 consecutive days;
12. Hereditary bleeding tendency or coagulopathy;
13. Digestive diseases such as active gastrointestinal ulcer, ulcerative colitis,intestinal obstruction, or other conditions that the investigator determines may causegastrointestinal bleeding or perforation
14. Allogeneic organ transplantation (except corneal transplantation) or allogeneichematopoietic stem cell transplantation is known;
15. Known allergy to oxaliplatin, capecitabine, sindilizumab or bevacizumab activeingredients or excipients;
16. Patients with multiple factors affecting oral medication (such as inability toswallow, post-gastrointestinal resection, chronic diarrhea and intestinalobstruction);
17. Has not fully recovered from toxicity and/or complications associated with anyintervention prior to initiation of treatment (i.e., ≤ grade 1 or baseline, excludingfatigue or hair loss);
18. Known history of human immunodeficiency virus (HIV) infection (i.e. HIV 1/2 antibodypositive);
19. Untreated active hepatitis B;
20. Active HCV-infected subjects (HCV antibody positive and HCV-RNA level above thedetection limit);
21. Received live vaccine within 30 days prior to initial administration (cycle 1, day 1); Note: Acceptance of injectable inactivated virus vaccine against seasonal influenza ispermitted within 30 days prior to first administration; Intranasally administered liveattenuated flu vaccines are not allowed.
22. Pregnant or lactating women;
23. Grade II or above peripheral neuropathy according to NCI CTCAE standards;
24. Patients undergoing strong CYP3A4 inducers;
25. The presence of any serious or uncontrollable systemic disease;
26. Any medical history or disease evidence that may interfere with the study results,prevent the subjects from participating fully in the study, abnormal values oftreatment or laboratory tests, or other conditions that the investigator considersinappropriate for the study because of other potential risks that the investigatorconsiders inappropriate for the study.