The Efficacy of Bevacizumab and Serplulimab Combined With Recombinant Mutant HumanTumor Necrosis Factor(rmhTNF-NC) in the Treatment of Malignant Ascites

Inclusion Criteria:

• Age ≥18 years old, gender unlimited;

• Malignant ascites confirmed by histology or cytology as originating from digestivesystem tumors (malignant confirmed by ascites cytology or clinically diagnosed asperitoneal metastases by imaging and symptoms);

• Patients with more than a moderate amount of abdominal fluid, who have failedinitial treatment or have been treated with conventional chemotherapy drugs and/orbiological response modulators intravenously. Moderate ascites is defined as:

• B ultrasound examination of ascites ≥3cm in lying position;

• Accompanied by clinical symptoms (chest tightness, shortness of breath,abdominal distension and discomfort, which were judged by researchers to berelated to abdominal fluid accumulation);

• ECOG physical status is 0-2;

• Expected survival time >3 months;

• Cardiopulmonary function is basically normal;

• For adequate organ function, subjects must meet the following laboratory criteria:

• Peripheral blood imaging: WBC≥4.0×109/L, PLT≥80×109/L, Hb≥90g/L;

• Renal function: serum creatinine ≤2×ULN and creatinine clearance (calculated byCockcroft-Gault formula) ≥40 ml/min;

• Liver function: total bilirubin ≤1.5× upper limit of normal value (ULN); Ortotal bilirubin >ULN but direct bilirubin ≤ ULN; Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or AST ≤5×ULN in patientswith liver metastasis);

• Good coagulation function, defined as International standardized ratio (INR) orprothrombin time (PT) ≤1.5 times ULN;

• Thyroid stimulating hormone (TSH) ≤ULN; If abnormal, T3 and T4 levels and clinicalmanifestations should be investigated, and comprehensive assessment of non-acuteactivity can be included;

• Non-surgical sterilization or female patients of reproductive age who are requiredto use a medically approved contraceptive method (such as an IUD, contraceptive pillor condom) during the study treatment period and for 6 months after the end of thestudy treatment period; Women of reproductive age who were not surgically sterilizedhad to be negative for serum or urine HCG within 7 days prior to study enrollment.And must be non-lactation period; For men whose partners are women of childbearingage, effective contraception should be used during the trial and within 6 monthsafter the last administration of the study drug;

• Voluntarily enrolled in this study, with good compliance, signed written informedconsent, and able to cooperate with follow-up observation.

Exclusion Criteria:

• History of allergy to tumor necrosis factor and its derivatives, bevacizumabanalogues, and Serplulimab;

• Malignant diseases other than digestive tract neoplasms were diagnosed within 5years prior to initial administration (excluding radical basal cell carcinoma of theskin, squamous epithelial carcinoma of the skin, and/or carcinoma in situ afterradical resection);

• Received any other investigational drug therapy or participated in an interventionalclinical investigator within 7 days prior to initial dosing; Or received anti-tumordrug treatment (including Chinese herbal medicine with anti-tumor indication) within 7 days prior to the first use of the study drug;

• Pregnant or lactating women, women of childbearing age who did not want to usecontraception during the study period; Or the man is unwilling to use effectivecontraception during treatment and during the following 1 year;

• Significant damage to the function of important organs;

• Patients with obvious bleeding tendency;

• Clinically significant or uncontrolled heart disease, including unstable anginapectoris, acute myocardial infarction within 6 months prior to first dosing, NewYork Heart Association Class III/IV congestive heart failure, and uncontrolledarrhythmia (in subjects who are allowed to wear a pacemaker or have atrialfibrillation and have a well-controlled heart rate);

• Presence of ECG changes or medical history that investigators consider clinicallysignificant; Screening QTcF interval >480 ms, subjects with indoor block (QRSinterval >120 ms) can use JTc interval instead of QTc interval (if JTc is usedinstead of QTc, JTc must be ≤340 ms);

• Uncontrolled hypertension, systolic blood pressure >160 mmHg or diastolic bloodpressure >100 mmHg after optimal medical treatment, history of hypertensive crisisor hypertensive encephalopathy;

• Severe acute infection that is not under control; The patient is having fever (> 38℃), or has suppurative and chronic infection, and the wound is prolonged and doesnot heal;

• Patients with encapsulated abdominal effusion confirmed by imaging; A definitediagnosis of abdominal infection;

• Persons infected with acute or chronic active hepatitis B or hepatitis C, hepatitisB virus (HBV) DNA>2000IU/ml or 104 copies /ml; Hepatitis C virus (HCV) RNA> 103copies /ml; Hepatitis B surface antigen (HbsAg) and anti-HCV antibodies were bothpositive. After nucleotide antiviral therapy, those who were lower than the abovecriteria could be included in the group. A known history of human immunodeficiencyvirus (HIV) infection or a confirmed positive immunotest result;

• Patients with obvious evidence of bleeding tendency or history within 3 months priorto enrollment (hemorrhage >30 mL within 3 months, hematemesis, stool, and blood inthe stool), hemoptysis (>5 mL fresh blood within 4 weeks); People with a history ofinherited or acquired bleeding or coagulation disorders. Have clinically significantbleeding symptoms or definite bleeding tendency within 3 months, such asgastrointestinal bleeding, hemorrhagic gastric ulcer, etc.; Arterial or venousthrombotic disease was present 6 weeks before enrollment;

• Known history of allogeneic organ transplantation and allogeneic hematopoietic stemcell transplantation;

• Had a major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4weeks prior to the first dose of study therapy or expected to require major surgeryduring study therapy;

• Complications of toxicity and/or major surgery have not fully recovered beforestarting treatment;

• Women who are pregnant or nursing, or who are expected to become pregnant or givebirth during the study period from screening visits to completion of safetyfollow-up visits (male subjects to 90 days after the last dosing);

• Radiotherapy was received within 4 weeks prior to the first administration of thestudy drug. Subjects must have fully recovered from radiation-related toxicitieswithout the need for corticosteroid therapy, confirming the rule out of radiationpneumonia. For palliative radiotherapy for non-CNS disease, a 2-week washout periodis allowed;

• Patients with uncontrollable neurological, mental illness or mental disorder, poorcompliance, unable to cooperate with and describe the response to treatment;Patients with uncontrolled primary brain tumor or central nervous metastases, withobvious cranial hypertension or neuropsychiatric symptoms;

• There are other conditions that researchers consider inappropriate to participate inthis experiment.