Toripalimab,Celecoxib and Regorafenib in the Treatment of Refractory Advanced Colorectal Cancer

Inclusion Criteria:

1. With subject's consent and signed informed consent form, willing and capable of following planned visits, research treatments, laboratory tests, and other trial procedures
2. Subjects diagnosed with colon or rectal adenocarcinoma by pathology or cytology have evidence of locally advanced lesions or metastases that cannot be surgically removed, without liver metastasis, and all other histological types are excluded.
3. Age 18 and above.
4. The subject has received at least second-line standard chemotherapy in the past and has failed. These standard treatment protocols must include fluorouracil, Oxaliplatin, irinotecan, and Bevacizumab. Subjects with left colon cancer RAS/BRAF V600E genotype of wild type must have received Cetuximab or Panitumumab and other Epidermal growth factor receptor inhibitors. The definition of treatment failure is: disease progression or intolerable toxic side effects occur during the treatment process or within 3 months after the last treatment (One or more chemotherapy drugs with a duration of ≥ 1 cycle for each frontline treatment until the disease progresses; adjuvant/neoadjuvant treatment is allowed in the early stage. If there is recurrence or metastasis during the adjuvant/neoadjuvant treatment or within 6 months after completion, adjuvant/neoadjuvant treatment is considered a failure of frontline systemic chemotherapy for advanced diseases.
5. The Eastern Cancer Cooperative Group's Physical Fitness Score (ECOG) is 0-1 points.
6. Clearly identify measurable lesions that meet the requirements of the evaluation criteria for solid tumor efficacy (RECIST version 1.1)
7. Based on the following laboratory test values obtained during the screening period, appropriate organ function is achieved: white blood cell count ≥ 3.3 × 109/L, neutrophil count ≥ 1.5 × 109/L, platelet count ≥ 75 × 109/L, serum total bilirubin ≤ 1.5 × Upper limit of normal value (UNL), Aspartate transaminase or alanine aminotransferase ≤ 2.5 × UNL (liver metastasis subjects should be ≤ 5 × ULN), serum creatinine ≤ 1.5 × UNL.
8. Female subjects of childbearing age must carry out a serum Pregnancy test within 3 days before starting the study medication, and the result is negative, and are willing to use a medically approved effective contraceptive measure (such as Intrauterine device, contraceptives or condoms) during the study period and within 3 months after the last administration of the study medication.For male subjects whose partners are women of childbearing age, they should undergo surgical sterilization or agree to use effective methods of contraception during the study period and within 3 months after the last study administration.

Exclusion Criteria:

1. Previous or concurrent existence of other active malignant tumors (except malignant tumors that have received cured therapy and have not developed for more than 5 years or Carcinoma in situ that can be cured through adequate treatment);
2. At present, there are duodenal ulcer, Ulcerative colitis, Bowel obstruction and other digestive tract diseases or other conditions that may cause gastrointestinal bleeding or perforation as determined by researchers.
3. Thrombosis or embolism events occurred within 6 months before the study, such as cerebrovascular accident (including transient ischemic attack), Pulmonary embolism, Deep vein thrombosis.
4. Within the 6 months prior to enrollment in the study, the following conditions occurred: myocardial infarction, severe/unstable angina, NYHA grade 2 or above cardiac insufficiency, clinically significant supraventricular or ventricular arrhythmias, and symptomatic congestive heart failure.
5. Systemic use of antibiotics for ≥ 7 days within 4 weeks prior to enrollment in the study, or unexplained fever \>38.5°C occurring during the screening period/before the first administration (according to the investigator's judgment, fever caused by tumor can be enrolled).
6. Major operations such as laparotomy, thoracotomy, organ removal through Laparoscopy or severe trauma were performed within 4 weeks before the study (Surgical incision should be completely healed before randomization);
7. Within 7 days prior to enrollment in the study, there were uncontrollable pleural effusion, ascites, or pericardial effusion after effective treatment.
8. Immunosuppressive drugs were used within 7 days before the enrollment study, excluding nasal and inhaled Corticosteroid or systemic Sex hormone hormones with physiological dose (i.e. no more than 10mg /d prednisone or other Corticosteroid with physiological dose of equivalent drugs).
9. The general term standard for adverse events (NCICTCAE Version 5.0) caused by any previous treatment that has not yet subsided has toxicity of grade 2 or above (except anemia, hair loss, skin pigmentation and peripheral neurotoxicity related to Oxaliplatin).
10. There are any active, known or suspected autoimmune diseases. Subjects who were in a stable state at the time of enrollment and did not need systemic immunosuppression treatment, such as type I diabetes, hypothyroidism only requiring hormone replacement treatment, and skin diseases that did not need systemic treatment (such as Vitiligo, psoriasis, and alopecia) are allowed.
11. There are Interstitial lung disease, non infectious pneumonia or uncontrollable systemic diseases (such as diabetes, hypertension, Pulmonary fibrosis and acute pneumonia).
12. HIV (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreated active hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ml; hepatitis C, defined as HCV-RNA higher than the detection limit of the analytical method) or co infection of hepatitis B and C.
13. Previously received antibodies against Programmed cell death protein-1 (PD-1) or its ligand (PD-L1), antibodies against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), or other drugs/antibodies that act on the costimulation or checkpoint pathway of T cells.
14. Previous treatment with regofinib.
15. Medical history of known or suspected allergy to any relevant Drug allergy used in the study.
16. Pregnant or lactating women.
17. Women of childbearing age who have not used or refused to use effective non hormonal contraceptive methods (\<2 years after their last menstrual period) or men who are at risk of giving birth.
18. The presence of other serious physical or mental illnesses or laboratory examination abnormalities may increase the risk of participating in the study, or interfere with the results of the study, as well as subjects deemed unsuitable by the researcher for participation in this study。