Treatment of Pyroptosis-inducible Newcasstle Disease Oncolytic Virus (PIN) Plus Anti-PD1 in Refractory Advanced Primary Hepatocellular Carcinoma---An Open Label Single Arm Phase I Clinical Trial.
In this single-center,open-label, phase I study, the safety and efficacy of PIN in combination with programmed cell death protein antibody (anti-PD1) therapeutic regimen will be evaluated in patients with refractory primary advanced hepatocellular carcinoma(HCC) . A total of 25 to 30 patients are planned to be enrolled and receive PIN plus anti-PD1 combined treatment. It aims to: 1).assess the safety and antitumor effects of the above combined treatment regimen. 2).detect the dynamic changes and molecular characteristics of PIN-induced CD8+ T cells with special phenotype in peripheral blood (PB) and transformation of tumor microenvironment (TME) after the treatment with PIN. 3).evaluate the immunological or clinical predictive biomarkers for toxicity and efficacy.
• Age 18-75 (inclusive).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Estimated life expectancy of more than 3 months.
• Histopathological /cytological or diagnosed clinically confirmed locally advanced or metastatic HCC having undergone treatments recommended by the Primary Liver CancerDiagnosis and Treatment Guidelines (2024 Edition) ,which is refractory/relapsed after and/or intolerant of standard therapies (including targeted therapy and immunotherapy) or for which no subsequent standard therapy exists.
• At least one measurable lesion at baseline according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1).
• Patients with injectable lesions (those suitable for direct injection or injection with the assistance of medical imaging), defined as follows: at least one injectable lesion in the skin, mucous membrane, subcutaneous tissue, lymph node or visceral organ with a longest diameter ≥10 mm.
• Subjects are willing to accept tumor rebiopsy in the process of this study.
• Barcelona Clinic Liver Cancer (BCLC) stage ≤C.
• Adequate organ function as defined by the following criteria:
‣ Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L, Platelet count ≥50 x 10\^9/ L, hemoglobin (Hgb) ≥ 80g/L ;
⁃ Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min;
⁃ Serum aspartate amino transferase (AST) and alanine aminotransferase (ALT), ≤5 x ULN ; Total serum bilirubin ≤3 x ULN);
⁃ Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings;
⁃ International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN;
⁃ Baseline oxygen saturation \>91% on room air.
• • Patients with chronic or acute hepatitis B virus (HBV) infection \[ as characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥20 IU/ml) \] must receive effective antiviral treatment before enrollment and during the treatment period, and their HBV DNA levels must be dynamically monitored during each treatment cycle.
‣ Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (\<20 IU/ml) do not require anti-viral therapy prior to enrollment.however, these subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥20 IU/ml).
⁃ Subjects with chronic infection by hepatitis C virus (HCV), who are untreated, are allowed on study. In addition, subjects with successful HCV treatment are allowed, as long as 4 weeks have passed between completion of HCV therapy and start of study drug.
⁃ Previous treatments must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to \<= grade 1 Toxicity (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
⁃ Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
⁃ Voluntarily participate in this clinical trial and sign an informed consent form.