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 offollowing planned visits, research treatments, laboratory tests, and other trialprocedures
2. Subjects diagnosed with colon or rectal adenocarcinoma by pathology or cytology haveevidence 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 andhas failed. These standard treatment protocols must include fluorouracil, Oxaliplatin,irinotecan, and Bevacizumab. Subjects with left colon cancer RAS/BRAF V600E genotypeof wild type must have received Cetuximab or Panitumumab and other Epidermal growthfactor receptor inhibitors. The definition of treatment failure is: diseaseprogression or intolerable toxic side effects occur during the treatment process orwithin 3 months after the last treatment (One or more chemotherapy drugs with aduration of ≥ 1 cycle for each frontline treatment until the disease progresses;adjuvant/neoadjuvant treatment is allowed in the early stage. If there is recurrenceor metastasis during the adjuvant/neoadjuvant treatment or within 6 months aftercompletion, adjuvant/neoadjuvant treatment is considered a failure of frontlinesystemic 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 evaluationcriteria 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 alanineaminotransferase ≤ 2.5 × UNL (liver metastasis subjects should be ≤ 5 × ULN), serumcreatinine ≤ 1.5 × UNL.
8. Female subjects of childbearing age must carry out a serum Pregnancy test within 3days before starting the study medication, and the result is negative, and are willingto use a medically approved effective contraceptive measure (such as Intrauterinedevice, contraceptives or condoms) during the study period and within 3 months afterthe last administration of the study medication.For male subjects whose partners arewomen of childbearing age, they should undergo surgical sterilization or agree to useeffective methods of contraception during the study period and within 3 months afterthe last study administration.

Exclusion Criteria:

1. Previous or concurrent existence of other active malignant tumors (except malignanttumors that have received cured therapy and have not developed for more than 5 yearsor Carcinoma in situ that can be cured through adequate treatment);
2. At present, there are duodenal ulcer, Ulcerative colitis, Bowel obstruction and otherdigestive tract diseases or other conditions that may cause gastrointestinal bleedingor perforation as determined by researchers.
3. Thrombosis or embolism events occurred within 6 months before the study, such ascerebrovascular accident (including transient ischemic attack), Pulmonary embolism,Deep vein thrombosis.
4. Within the 6 months prior to enrollment in the study, the following conditionsoccurred: myocardial infarction, severe/unstable angina, NYHA grade 2 or above cardiacinsufficiency, clinically significant supraventricular or ventricular arrhythmias, andsymptomatic congestive heart failure.
5. Systemic use of antibiotics for ≥ 7 days within 4 weeks prior to enrollment in thestudy, or unexplained fever >38.5°C occurring during the screening period/before thefirst administration (according to the investigator's judgment, fever caused by tumorcan be enrolled).
6. Major operations such as laparotomy, thoracotomy, organ removal through Laparoscopy orsevere trauma were performed within 4 weeks before the study (Surgical incision shouldbe completely healed before randomization);
7. Within 7 days prior to enrollment in the study, there were uncontrollable pleuraleffusion, ascites, or pericardial effusion after effective treatment.
8. Immunosuppressive drugs were used within 7 days before the enrollment study, excludingnasal and inhaled Corticosteroid or systemic Sex hormone hormones with physiologicaldose (i.e. no more than 10mg /d prednisone or other Corticosteroid with physiologicaldose of equivalent drugs).
9. The general term standard for adverse events (NCICTCAE Version 5.0) caused by anyprevious treatment that has not yet subsided has toxicity of grade 2 or above (exceptanemia, hair loss, skin pigmentation and peripheral neurotoxicity related toOxaliplatin).
10. There are any active, known or suspected autoimmune diseases. Subjects who were in astable state at the time of enrollment and did not need systemic immunosuppressiontreatment, such as type I diabetes, hypothyroidism only requiring hormone replacementtreatment, 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 uncontrollablesystemic diseases (such as diabetes, hypertension, Pulmonary fibrosis and acutepneumonia).
12. HIV (HIV) infection or known acquired immunodeficiency syndrome (AIDS), untreatedactive hepatitis (hepatitis B, defined as HBV-DNA ≥ 500 IU/ml; hepatitis C, defined asHCV-RNA higher than the detection limit of the analytical method) or co infection ofhepatitis B and C.
13. Previously received antibodies against Programmed cell death protein-1 (PD-1) or itsligand (PD-L1), antibodies against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), or other drugs/antibodies that act on the costimulation or checkpointpathway of T cells.
14. Previous treatment with regofinib.
15. Medical history of known or suspected allergy to any relevant Drug allergy used in thestudy.
16. Pregnant or lactating women.
17. Women of childbearing age who have not used or refused to use effective non hormonalcontraceptive methods (<2 years after their last menstrual period) or men who are atrisk of giving birth.
18. The presence of other serious physical or mental illnesses or laboratory examinationabnormalities may increase the risk of participating in the study, or interfere withthe results of the study, as well as subjects deemed unsuitable by the researcher forparticipation in this study。