Bevacizumab, Sintilimab, Cetuximab and Irinotecan in Refractory RAS Wild-type Metastatic Colorectal Cancer: BOND-4 Trial

Inclusion Criteria:

* Metastatic and unresectable colorectal adenocarcinom;
* RAS wild-type and MSS tumor;
* Measurable lesions;
* Failed to at least two lines of standard treatment containing fluoropyrimidine, irinotecan and bevacizumab;
* Eastern Cooperative Oncology Group performance status 2 or less;
* White blood cell≥ 3\*10\^9/L, neutrophil≥ 1.5\*10\^9/Lplatelet count≥75\*10\^9/L, hemoglobin≥60g/L;
* Total serum bilirubin≤upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5\*ULN or ≤5\*ULN for subjects with liver metastasis;
* Creatinine ≤ ULN or creatinine clearance ≥ 80 mL/min;
* Urinary protein negative or 24-hour urinary protein ≤ 2g;
* Activated partial thromboplastin time≤ULN and international normalized ratio≤1.5;
* Any major surgery ≥ 4 weeks and any minor surgery ≥ 1 week and fully recovered from the procedure;
* Life expectancy \> 3 months;
* Provide fully informed written consent;

Exclusion Criteria:

* Other aggressive malignancies within 3 years (Exceptions: non-melanoma skin cancer or carcinoma-in-situ of the cervix that has been treated);
* Allergy or intolerance to any of the study drugs;
* Human immunodeficiency virus positive;
* Concurrent anti-cancer therapy including radiation therapy, chemotherapy, targeted agents or biological agents not otherwise specified within two weeks;
* Malignant bowel obstruction;
* Prior treatment with PD-1 antibody;
* Autoimmune diseases;
* Significant bleeding events or pre-existing bleeding diathesis within 6 months (unless the source of bleeding has been resected);
* Gastrointestinal perforation within 12 months;
* Serious or non-healing wound, ulcer, or bone fracture;
* Blood pressure \>= 160/90 mmHg after active anti-hypertensive therapy;
* Arterial or venous thrombotic or embolic events within 6 months (including but not limited to transient ischemic attack, cerebrovascular accident, unstable angina or myocardial infarction);
* Uncontrolled illness including active infection, symptomatic congestive heart failure, cardiac arrhythmia, respiratory failure, symptomatic pulmonary fibrosis, interstitial pneumonitis or psychiatric illness that may interfere with the conduct of the study;
* Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis;
* Any of the following: pregnant, nursing, childbearing potential but unwilling to employ contraception.