Safety and Tolerability Study of Recombinant L-IFN Adenovirus Injection in Patients With Recurrent Glioblastoma

Inclusion Criteria:

1.Voluntarily sign the informed consent and follow the requirements of the protocol; 2.18years old ≤ age ≤75 years old, male or female; 3. Expected survival time ≥12 weeks; 4.KPSscore ≥50 before treatment; 5. Patients with pathologically and/or cytologically confirmedglioblastoma; After conventional radiation and/or systemic therapy, the disease recurred.PETCT/MRI of the head within 14 days before screening confirmed at least one enhancementlesion ≥1 cm in length. 6. The patient has recovered from the toxic effects of the last treatment before the firstdose (CTCAE≤1, except for special conditions such as "alopecia" and "pigmentation"), andthe corresponding AE is judged by the investigator to be not a safety risk; 7. Organ andbone marrow function levels must meet the following requirements:

1. Bone marrow: Absolute neutrophil count (ANC) ≥1.5×10^9/L, platelet count ≥100×10^9/L,hemoglobin ≥90 g/L, and no platelet or red blood cell transfusion within 14 daysbefore the first dose; No blood transfusion or biological response regulators (such asgranulocyte stimulating growth factor, erythrocyte growth factor, interleukin-11,etc.) within 14 days before the first dose;
2. Liver function: No history of cirrhosis (Child-Pugh class B, C decompensatedcirrhosis) Patients without liver metastasis were required to have serum totalbilirubin (TBIL) ≤1.5× upper limit of normal (ULN), alanine aminotransferase (ALT) andaspartate aminotransferase (AST) ≤2.5×ULN. Patients with liver metastasis requiredTBIL ≤1.5×ULN, ALT and AST≤5×ULN;
3. Renal function: serum creatinine ≤1.5×ULN or creatinine clearance ≥50 ml/ minute (Cockcorft-Gault formula) Qualitative urine protein ≤1+; If urinary proteinqualitative ≥2+，24-hour urinary protein quantitative test is required. Theinvestigators determined the enrollment according to the examination results.
4. Coagulation: prothrombin time (PT) ≤1.5 times ULN An international normalized ratio (INR) of 1.5×ULN or less and an activated partial thromboplastin time (APTT) of 1.5×ULN or less (except for those receiving therapeutic anticoagulants); 8. Femaleparticipants of childbearing age must have taken a serum pregnancy test with anegative result within 3 days before starting study medication and be willing to use amedically approved, highly effective contraceptive (e.g., IUD, contraceptive pill, orcondom) during the study and for 5 months after last administration of studymedication; For male subjects whose partner was a woman of childbearing age, consentwas given to use an effective method of contraception for the duration of the studyand for 5 months after the last study dose.

Exclusion Criteria:

1. Previous or current history of other types of malignant tumors, except for thefollowing:
2. radical cutaneous basal cell carcinoma, superficial bladder cancer, cutaneoussquamous cell carcinoma, or cervical cancer in situ;
3. second primary cancer that has been cured with no recurrence within 5 years;
4. Known allergy to the study drug or any of its excipients, or a history of unexplainedsevere allergic reaction;
5. Any contraindications to gadolinium contrast-enhanced MRI, such as personal use of apacemaker, infusion pump, or allergy to MRI contrast media;
6. Any contraindications to implantation of Ommaya reservoir;
7. Received any of the following treatments or medications before the first studytreatment:
8. major surgery or major trauma within 4 weeks before the first study drug. (Majorsurgery is defined as any invasive procedure that involves extensive resection orthat requires opening of mesothelial cell barriers (e.g., pleural space,peritoneum, meninges). However, biopsies needed for diagnosis were permitted.Severe trauma is a wound, ulcer or fracture that does not heal;
9. administration of live attenuated vaccine within 4 weeks before or planned forthe duration of the first study drug;
10. medium (adult) drug treatment with anti-tumor indications within 2 weeks beforethe first study drug treatment;
11. antineoplastic therapy (including chemotherapy, radiotherapy, immunotherapy,targeted therapy, biological therapy or tumor embolization) within 4 weeks beforethe first dose; For oral fluorouracil and endocrine therapy, drug withdrawal ≤2weeks; In the case of nitrosourea, mitomycin or monoclonal antibody, drugwithdrawal ≤6 weeks. If washout time is insufficient due to schedule or PKcharacteristics of the drug, it needs to be discussed with the partner;
12. Patients with symptoms, disseminated to viscera, and risk of life-threateningcomplications in a short period of time, patients with pleural effusion, peritonealeffusion, and pericardial effusion who underwent puncture and drainage within threeweeks before the first administration;
13. Subjects with active or preexisting autoimmune diseases (e.g., systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroiddisease, multiple sclerosis, vasculitis, glomerulonephritis, etc.) or those at highrisk (e.g., organ transplant recipients requiring immunosuppressive therapy). However,subjects with the following conditions were allowed:
14. patients with type I diabetes who are stable on fixed doses of insulin;
15. autoimmune hypothyroidism with hormone replacement therapy only;
16. skin conditions requiring no systemic treatment (e.g. eczema, rashes coveringless than 10% of the body surface, psoriasis without eye symptoms, etc.);
17. patients who have resolved childhood asthma/allergy without intervention inadulthood;
18. Cardiovascular disease within 6 months before screening meets any of the followingcriteria:
19. congestive heart failure with New York Heart Association (NYHA) class Ⅱ or above;Left ventricular ejection fraction (LVEF) < 50%;
20. severe arrhythmias requiring medical treatment;
21. QTcF (Fridericia's formula) > 450 msec in a man or > 470 msec in a woman, or thepresence of risk factors for torsdes pointes, such as hypokalemia, a familyhistory of long QT syndrome, or a family history of arrhythmias (e.g., theWolff-White syndrome), as judged by the investigator to be clinicallysignificant;
22. a history of myocardial infarction or severe/unstable angina within 6 monthsbefore treatment;
23. a history of thromboembolic events of grade ≥3 within the past 2 years orreceiving thrombolytic or anticoagulant therapy due to a high risk of thrombosis;
24. Patients with sudden lung disease, interstitial lung disease or pneumonia, pulmonaryfibrosis, acute lung disease, etc. which could not be controlled after treatment,except for local interstitial pneumonia induced by radiotherapy;
25. Uncontrolled systemic diseases, such as diabetes (fasting blood glucose ≥13.3mM),hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100mmHg), etc.;
26. Have a history of human immunodeficiency virus infection or other acquired orcongenital immunodeficiency diseases, or have a history of organ transplantation orstem cell transplantation; Except for those who do not require immunosuppressivetherapy, such as corneal transplantation;
27. Evidence of active infection:
28. Hepatitis B (HBsAg positive, HBV-DNA≥500IU/ml and abnormal liver function);
29. Hepatitis C (HCV-Ab positive, HCV-RNA higher than the detection limit ofanalytical method and abnormal liver function);
30. Systemic use of anti-infective agents for ≥7 days within 4 weeks before the firstdose or unexplained fever > 38.5°C during screening/before the first dose (according to the investigator's judgment, fever caused by cancer could beenrolled);
31. Patients with active pulmonary tuberculosis infection detected by medical historyor CT examination, or with a history of active pulmonary tuberculosis infectionwithin 1 year before enrollment, or with a history of active pulmonarytuberculosis infection more than 1 year before enrollment but without regulartreatment;
32. A definite history of a previous neurological or mental disorder or a known history ofpsychotropic substance abuse, alcohol abuse or drug use;
33. Received any investigational drug within 4 weeks before the first dose or was enrolledin another clinical study (except if the patient was enrolled in an observational,noninterventional clinical study or was in the follow-up period of an interventionalclinical study; or more than 5 half-lives of the last study medication);
34. Women who are pregnant or lactating, or who have a positive baseline pregnancy test;
35. Patients deemed by the investigator to be ineligible for inclusion in the study.