| Eligibility |
Inclusion Criteria:
1. Before the implementation of any trial-related procedures, sign a written informed
consent 2. Male or female =18 years old, =75 years old 3. Gallbladder carcinoma confirmed
by histology or cytology 4. No previous systemic anti-tumor therapy (radiotherapy,
chemotherapy, targeted or immunotherapy, etc.) 5. Expected survival time > 3 months 6. At
least 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:
1. Absolute value of neutrophils (ANC) = 1.5x109/L and platelets = 90×109/L without using
granulocyte colony-stimulating factor in the past 14 days;
2. Hemoglobin > 9g/dL without blood transfusion or use of erythropoietin in the past 21
days;
3. Total bilirubin = 3 × upper limit of normal (ULN);
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are =2.5×ULN
(patients with liver metastases are allowed ALT or AST =5×ULN);
5. Alkaline phosphatase (AKP) =2.5×ULN
6. Creatinine clearance rate (calculated using the Cockcroft-Gault formula) = 50 ml/min;
7. Good coagulation function, defined as international normalized ratio (INR) or
prothrombin time (PT) = 1.5 times ULN;
8. Normal thyroid function, defined as thyroid-stimulating hormone (TSH = 10) within the
normal range; thyroid dysfunction without clinical significance after thyroid hormone
supplementation can also be included.
9. Myocardial enzyme spectrum is within the normal range (such as simple laboratory
abnormalities that are judged by the investigator to have no clinical significance are
also allowed to enter the group); 9. For female subjects of childbearing age, they
should receive a urine or serum pregnancy test within 3 days before receiving the
first study drug administration (day 1 of cycle 1) and the result is negative. If the
urine pregnancy test result cannot be confirmed negative, a blood pregnancy test will
be ordered. Women of non-reproductive age are defined as postmenopausal for at least 1
year, or who have undergone surgical sterilization or hysterectomy 10. If there is a
risk of pregnancy, all subjects (regardless of male or female) need to use
contraceptive measures with an annual failure rate of less than 1% during the entire
treatment 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 the
first administration (excluding radically cured skin basal cell carcinoma, skin
squamous cell carcinoma, and/or radically resected carcinoma in situ, radically cured
thyroid papillary carcinoma can also be included after surgery);
2. Currently participating in interventional clinical research treatment, or receiving
other research drugs or using research devices within 4 weeks before the first
administration;
3. Active autoimmune disease requiring systemic treatment (such as the use of
disease-modifying drugs, glucocorticoids or immunosuppressants) occurred before the
first dose. Replacement therapies (eg, thyroxine, insulin, or physiologic
glucocorticoids for adrenal or pituitary insufficiency) are not considered systemic
therapy. Known history of primary immunodeficiency. Only patients with autoimmune
antibody positive need to confirm whether there is an autoimmune disease according to
the investigator's judgment;
4. Active hemoptysis (spitting up at least 2.5ml or 1/2 teaspoon of fresh blood) within 3
months before the first study drug administration, and active gastrointestinal
bleeding within 3 months before administration;
5. Imaging shows tumor invasion/infiltration of large blood vessels or bleeding tendency
assessed by researchers or radiologists;
6. Received major surgical treatment within 4 weeks before the first study drug
administration (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 to
inhibit 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 10
consecutive days Note: The prophylactic use of small doses of anticoagulants is
allowed: on the premise that the international normalized ratio (INR) of prothrombin
time is =1.5, small doses of warfarin (=1 mg/d) and low doses of heparin are allowed
for 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 or
other routes of topical glucocorticoid) or any other form of immunosuppressive therapy
within 4 weeks before the first dose of the study Note: Physiological doses of
glucocorticoids are permitted (=10 mg/day of prednisone or equivalent)
12. There is clinically uncontrollable pleural effusion/abdominal effusion (patients who
do not need drainage or stop drainage for 3 days without significant increase in
effusion can be enrolled)
13. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic
hematopoietic stem cell transplantation
14. Those who are known to be allergic to active ingredients or excipients of the study
drug sintilimab, bevacizumab, gemcitabine hydrochloride for injection, paclitaxel for
injection (albumin-bound type)
15. Has not recovered adequately from any intervention-induced toxicity and/or
complications (ie, = Grade 1 or reached baseline, excluding fatigue or alopecia) prior
to initiating treatment
16. Known history of human immunodeficiency virus (HIV) infection (ie HIV 1/2 antibody
positive)
17. Untreated active hepatitis B (defined as HBsAg positive and detection of HBV-DNA copy
number greater than the upper limit of normal value of the laboratory laboratory of
the research center)
Note: Hepatitis B subjects who meet the following criteria can also be enrolled:
1. If the HBV viral load before the first administration is <2.5×103 copies/ml (500
IU/ml), the subject should receive anti-HBV treatment during the entire study
treatment period
2. For subjects whose anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load are less
than the upper limit of normal value in the laboratory department of the research
center, they do not need to receive preventive anti-HBV treatment, but they need to be
closely monitored. Monitoring for viral reactivation 18. Subjects with active HCV
infection (HCV antibody positive and HCV-RNA level higher than the lower limit of
detection) 19. Except for those who have received live attenuated vaccines within 4
weeks before the first dose of the new crown vaccine 20. Pregnant or lactating women
21. Esophageal or gastric variceal bleeding events caused by portal hypertension in
the past 6 months; known severe (G3) varices in endoscopy within 3 months before the
first administration; evidence of portal hypertension (including Imaging examination
revealed 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. Any
life-threatening bleeding events occurred in the past 3 months, including the need for
blood transfusion therapy, surgery or local therapy, continuous drug therapy 23.
Arterial and venous thromboembolic events within the past 6 months, including
myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic
attack, pulmonary embolism, deep vein thrombosis or any other serious history of
thromboembolism. Implantable venous port or catheter-derived thrombosis, or
superficial venous thrombosis, unless the thrombus is stabilized after conventional
anticoagulant therapy 24. History of gastrointestinal perforation and/or fistula,
intestinal obstruction (including incomplete intestinal obstruction requiring
parenteral nutrition), extensive bowel resection (partial colon resection or extensive
small bowel resection, complicated by chronic diarrhea) within the past 6 months ,
Crohn's disease, ulcerative colitis, or long-term chronic diarrhea; 25. Presence of
any serious or uncontrolled systemic disease, such as:
1) Resting ECG has significant abnormalities in rhythm, conduction or morphology, and the
symptoms are severe and uncontrollable, such as complete left bundle branch block, heart
block above second degree, ventricular arrhythmia or with fast ventricular rate atrial
fibrillation 2) Unstable angina, congestive heart failure, New York Heart Association
(NYHA) grade = 2 chronic heart failure 3) Any arterial thrombosis, embolism or ischemia
occurred within 6 months before the selected treatment, such as myocardial infarction,
unstable angina, cerebrovascular accident or transient ischemic attack, etc.; 4) Received
major surgical operations (craniotomy, thoracotomy or laparotomy) or unhealed wounds,
ulcers or fractures within 4 weeks before the first administration. Received tissue biopsy
or other minor surgical procedures within 7 days before the first dose, except for
venipuncture for intravenous infusion 5) Unsatisfactory blood pressure control (systolic
blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg) 6) Active tuberculosis
7) Active or uncontrolled infection requiring systemic therapy 8) Clinically active
diverticulitis, abdominal abscess, gastrointestinal obstruction 9) Liver disease such as
cirrhosis, decompensated liver disease, acute or chronic active hepatitis 10) Poorly
controlled diabetes (fasting blood glucose (FBG) > 10mmol/L) 11) Urine routine prompts
urine protein = ++, and confirmed 24-hour urine protein quantity > 1.0 g; 12) Patients with
mental disorders who cannot cooperate with treatment 26. Medical history or disease
evidence that may interfere with the test results, prevent the subject from participating
in the whole study, abnormal treatment or laboratory test values, or other situations that
the investigator believes are not suitable for enrollment. The investigator believes that
there are other potential risks t
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