Multi-arm, Phase II Clinical Study of Intraperitoneal Injection of Recombinant Human Tumor Necrosis Factor, Bevacizumab Monoclonal Antibody, and Serplulimab for the Treatment of Malignant Ascites Patients With Standard Therapy Failure
1. More than half of peritoneal metastases are from digestive tract. Peritoneal metastasis has poor prognosis, poor treatment response and limited means. 2. rmhTNF-NC or bevacizumab are effective in the treatment of malignant pleuroabdominal effusion. 3, There is increasing evidence that PD-1/PD-L1 inhibitors in combination with vascular endothelial growth factor receptor (VEGFR) inhibitors have a complementary mechanism of action: VEGF pathway inhibitors normalize blood vessels in tumors and promote immune cell maturation and infiltration, thus playing a synergistic role with ICIs. The strategy of systemic immunotherapy combined with antivascular therapy has been confirmed by several large phase III clinical trials such as IMbrave-150. Basic studies have confirmed that uncontrolled tumor vessels in peritoneal metastasis and malignant ascites microenvironment also play an important role in promoting disease progression. Therefore, this project intends to explore the treatment of malignant abdominal effusion by local intraperitoneal injection of bevacizumab and PD-1 on the basis of rmhTNF-NC
• Age ≥18 years old, gender unlimited;
• Malignant ascites confirmed by histology or cytology as originating from digestive system tumors (malignant confirmed by ascites cytology or clinically diagnosed as peritoneal metastases by imaging and symptoms);
• Patients with more than a moderate amount of abdominal fluid, who have failed initial treatment or have been treated with conventional chemotherapy drugs and/or biological 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 be related 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 by Cockcroft-Gault formula) ≥40 ml/min;
⁃ Liver function: total bilirubin ≤1.5× upper limit of normal value (ULN); Or total bilirubin \>ULN but direct bilirubin ≤ ULN; Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or AST ≤5×ULN in patients with liver metastasis);
⁃ Good coagulation function, defined as International standardized ratio (INR) or prothrombin time (PT) ≤1.5 times ULN;
• Thyroid stimulating hormone (TSH) ≤ULN; If abnormal, T3 and T4 levels and clinical manifestations should be investigated, and comprehensive assessment of non-acute activity can be included;
• Non-surgical sterilization or female patients of reproductive age who are required to use a medically approved contraceptive method (such as an IUD, contraceptive pill or condom) during the study treatment period and for 6 months after the end of the study treatment period; Women of reproductive age who were not surgically sterilized had 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 childbearing age, effective contraception should be used during the trial and within 6 months after the last administration of the study drug;
• Voluntarily enrolled in this study, with good compliance, signed written informed consent, and able to cooperate with follow-up observation.