Combination of Gemcitabine, Albumin-paclitaxel , Sintilimab and Bevacizumab in Unresectable Gallbladder Cancer

Inclusion Criteria:

1. Before the implementation of any trial-related procedures, sign a written informedconsent 2. Male or female ≥18 years old, ≤75 years old 3. Gallbladder carcinoma confirmedby histology or cytology 4. No previous systemic anti-tumor therapy (radiotherapy,chemotherapy, targeted or immunotherapy, etc.) 5. Expected survival time > 3 months 6. Atleast 1 measurable lesion according to RECIST1.1 criteria 7. ECOG PS score of 0-1 8.Sufficient organ function, the subject needs to meet the following laboratory indicators:
2. Absolute value of neutrophils (ANC) ≥ 1.5x109/L and platelets ≥ 90×109/L without usinggranulocyte colony-stimulating factor in the past 14 days;
3. Hemoglobin > 9g/dL without blood transfusion or use of erythropoietin in the past 21days;
4. Total bilirubin ≤ 3 × upper limit of normal (ULN);
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are ≤2.5×ULN (patients with liver metastases are allowed ALT or AST ≤5×ULN);
6. Alkaline phosphatase (AKP) ≤2.5×ULN
7. Creatinine clearance rate (calculated using the Cockcroft-Gault formula) ≥ 50 ml/min;
8. Good coagulation function, defined as international normalized ratio (INR) orprothrombin time (PT) ≤ 1.5 times ULN;
9. Normal thyroid function, defined as thyroid-stimulating hormone (TSH ≤ 10) within thenormal range; thyroid dysfunction without clinical significance after thyroid hormonesupplementation can also be included.
10. Myocardial enzyme spectrum is within the normal range (such as simple laboratoryabnormalities that are judged by the investigator to have no clinical significance arealso allowed to enter the group); 9. For female subjects of childbearing age, theyshould receive a urine or serum pregnancy test within 3 days before receiving thefirst study drug administration (day 1 of cycle 1) and the result is negative. If theurine pregnancy test result cannot be confirmed negative, a blood pregnancy test willbe ordered. Women of non-reproductive age are defined as postmenopausal for at least 1year, or who have undergone surgical sterilization or hysterectomy 10. If there is arisk of pregnancy, all subjects (regardless of male or female) need to usecontraceptive measures with an annual failure rate of less than 1% during the entiretreatment period until 120 days after the last study drug administration

Exclusion Criteria:

1. Other malignant diseases outside the biliary tract diagnosed within 5 years before thefirst administration (excluding radically cured skin basal cell carcinoma, skinsquamous cell carcinoma, and/or radically resected carcinoma in situ, radically curedthyroid papillary carcinoma can also be included after surgery);
2. Currently participating in interventional clinical research treatment, or receivingother research drugs or using research devices within 4 weeks before the firstadministration;
3. Active autoimmune disease requiring systemic treatment (such as the use ofdisease-modifying drugs, glucocorticoids or immunosuppressants) occurred before thefirst dose. Replacement therapies (eg, thyroxine, insulin, or physiologicglucocorticoids for adrenal or pituitary insufficiency) are not considered systemictherapy. Known history of primary immunodeficiency. Only patients with autoimmuneantibody positive need to confirm whether there is an autoimmune disease according tothe investigator's judgment;
4. Active hemoptysis (spitting up at least 2.5ml or 1/2 teaspoon of fresh blood) within 3months before the first study drug administration, and active gastrointestinalbleeding within 3 months before administration;
5. Imaging shows tumor invasion/infiltration of large blood vessels or bleeding tendencyassessed by researchers or radiologists;
6. Received major surgical treatment within 4 weeks before the first study drugadministration (except for surgery for biopsy);
7. Severe unhealed wound ulcers or fractures;
8. Current or recent (within 10 days before receiving the first dose of the study drug)use of aspirin (>325mg/day) or other non-steroidal anti-inflammatory drugs known toinhibit platelet function for 10 consecutive days;
9. Current or recent (within 10 days before receiving the first dose of study drug)treatment with full-dose oral or parenteral anticoagulant or thrombolytic agent for 10consecutive days Note: The prophylactic use of small doses of anticoagulants isallowed: on the premise that the international normalized ratio (INR) of prothrombintime is ≤1.5, small doses of warfarin (≤1 mg/d) and low doses of heparin are allowedfor prophylactic purposes (≤12,000 U/d) or low-dose aspirin (≤100mg/d);
10. Have hereditary bleeding tendency or coagulation disorder, or history of thrombosis;
11. Are receiving systemic glucocorticoid therapy (excluding nasal spray, inhalation orother routes of topical glucocorticoid) or any other form of immunosuppressive therapywithin 4 weeks before the first dose of the study Note: Physiological doses ofglucocorticoids are permitted (≤10 mg/day of prednisone or equivalent)
12. There is clinically uncontrollable pleural effusion/abdominal effusion (patients whodo not need drainage or stop drainage for 3 days without significant increase ineffusion can be enrolled)
13. Known allogeneic organ transplantation (except corneal transplantation) or allogeneichematopoietic stem cell transplantation
14. Those who are known to be allergic to active ingredients or excipients of the studydrug sintilimab, bevacizumab, gemcitabine hydrochloride for injection, paclitaxel forinjection (albumin-bound type)
15. Has not recovered adequately from any intervention-induced toxicity and/orcomplications (ie, ≤ Grade 1 or reached baseline, excluding fatigue or alopecia) priorto initiating treatment
16. Known history of human immunodeficiency virus (HIV) infection (ie HIV 1/2 antibodypositive)
17. Untreated active hepatitis B (defined as HBsAg positive and detection of HBV-DNA copynumber greater than the upper limit of normal value of the laboratory laboratory ofthe research center) Note: Hepatitis B subjects who meet the following criteria can also be enrolled:
18. If the HBV viral load before the first administration is <2.5×103 copies/ml (500IU/ml), the subject should receive anti-HBV treatment during the entire studytreatment period
19. For subjects whose anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load are lessthan the upper limit of normal value in the laboratory department of the researchcenter, they do not need to receive preventive anti-HBV treatment, but they need to beclosely monitored. Monitoring for viral reactivation 18. Subjects with active HCVinfection (HCV antibody positive and HCV-RNA level higher than the lower limit ofdetection) 19. Except for those who have received live attenuated vaccines within 4weeks before the first dose of the new crown vaccine 20. Pregnant or lactating women
20. Esophageal or gastric variceal bleeding events caused by portal hypertension inthe past 6 months; known severe (G3) varices in endoscopy within 3 months before thefirst administration; evidence of portal hypertension (including Imaging examinationrevealed that the length of splenomegaly exceeds 10 cm and the platelets are less than 100×109/L), and the researchers evaluated the risk of bleeding as high 22. Anylife-threatening bleeding events occurred in the past 3 months, including the need forblood transfusion therapy, surgery or local therapy, continuous drug therapy 23.Arterial and venous thromboembolic events within the past 6 months, includingmyocardial infarction, unstable angina, cerebrovascular accident or transient ischemicattack, pulmonary embolism, deep vein thrombosis or any other serious history ofthromboembolism. Implantable venous port or catheter-derived thrombosis, orsuperficial venous thrombosis, unless the thrombus is stabilized after conventionalanticoagulant therapy 24. History of gastrointestinal perforation and/or fistula,intestinal obstruction (including incomplete intestinal obstruction requiringparenteral nutrition), extensive bowel resection (partial colon resection or extensivesmall bowel resection, complicated by chronic diarrhea) within the past 6 months ,Crohn's disease, ulcerative colitis, or long-term chronic diarrhea; 25. Presence ofany serious or uncontrolled systemic disease, such as:

1. Resting ECG has significant abnormalities in rhythm, conduction or morphology, and thesymptoms are severe and uncontrollable, such as complete left bundle branch block, heartblock above second degree, ventricular arrhythmia or with fast ventricular rate atrialfibrillation 2) Unstable angina, congestive heart failure, New York Heart Association (NYHA) grade ≥ 2 chronic heart failure 3) Any arterial thrombosis, embolism or ischemiaoccurred within 6 months before the selected treatment, such as myocardial infarction,unstable angina, cerebrovascular accident or transient ischemic attack, etc.; 4) Receivedmajor surgical operations (craniotomy, thoracotomy or laparotomy) or unhealed wounds,ulcers or fractures within 4 weeks before the first administration. Received tissue biopsyor other minor surgical procedures within 7 days before the first dose, except forvenipuncture for intravenous infusion 5) Unsatisfactory blood pressure control (systolicblood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg) 6) Active tuberculosis
2. Active or uncontrolled infection requiring systemic therapy 8) Clinically activediverticulitis, abdominal abscess, gastrointestinal obstruction 9) Liver disease such ascirrhosis, decompensated liver disease, acute or chronic active hepatitis 10) Poorlycontrolled diabetes (fasting blood glucose (FBG) > 10mmol/L) 11) Urine routine promptsurine protein ≥ ++, and confirmed 24-hour urine protein quantity > 1.0 g; 12) Patients withmental disorders who cannot cooperate with treatment 26. Medical history or diseaseevidence that may interfere with the test results, prevent the subject from participatingin the whole study, abnormal treatment or laboratory test values, or other situations thatthe investigator believes are not suitable for enrollment. The investigator believes thatthere are other potential risks t