Inclusion Criteria:
1.Voluntarily sign the informed consent and follow the requirements of the protocol; 2.18
years old ≤ age ≤75 years old, male or female; 3. Expected survival time ≥12 weeks; 4.KPS
score ≥50 before treatment; 5. Patients with pathologically and/or cytologically confirmed
glioblastoma; After conventional radiation and/or systemic therapy, the disease recurred.
PETCT/MRI of the head within 14 days before screening confirmed at least one enhancement
lesion ≥1 cm in length.
6. The patient has recovered from the toxic effects of the last treatment before the first
dose (CTCAE≤1, except for special conditions such as "alopecia" and "pigmentation"), and
the corresponding AE is judged by the investigator to be not a safety risk; 7. Organ and
bone 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 days
before the first dose; No blood transfusion or biological response regulators (such as
granulocyte 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 decompensated
cirrhosis) Patients without liver metastasis were required to have serum total
bilirubin (TBIL) ≤1.5× upper limit of normal (ULN), alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) ≤2.5×ULN. Patients with liver metastasis required
TBIL ≤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 protein
qualitative ≥2+，24-hour urinary protein quantitative test is required. The
investigators 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. Female
participants of childbearing age must have taken a serum pregnancy test with a
negative result within 3 days before starting study medication and be willing to use a
medically approved, highly effective contraceptive (e.g., IUD, contraceptive pill, or
condom) during the study and for 5 months after last administration of study
medication; For male subjects whose partner was a woman of childbearing age, consent
was given to use an effective method of contraception for the duration of the study
and for 5 months after the last study dose.
Exclusion Criteria:
1. Previous or current history of other types of malignant tumors, except for the
following:
1. radical cutaneous basal cell carcinoma, superficial bladder cancer, cutaneous
squamous cell carcinoma, or cervical cancer in situ;
2. second primary cancer that has been cured with no recurrence within 5 years;
2. Known allergy to the study drug or any of its excipients, or a history of unexplained
severe allergic reaction;
3. Any contraindications to gadolinium contrast-enhanced MRI, such as personal use of a
pacemaker, infusion pump, or allergy to MRI contrast media;
4. Any contraindications to implantation of Ommaya reservoir;
5. Received any of the following treatments or medications before the first study
treatment:
1. major surgery or major trauma within 4 weeks before the first study drug. (Major
surgery is defined as any invasive procedure that involves extensive resection or
that 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;
2. administration of live attenuated vaccine within 4 weeks before or planned for
the duration of the first study drug;
3. medium (adult) drug treatment with anti-tumor indications within 2 weeks before
the first study drug treatment;
4. antineoplastic therapy (including chemotherapy, radiotherapy, immunotherapy,
targeted therapy, biological therapy or tumor embolization) within 4 weeks before
the first dose; For oral fluorouracil and endocrine therapy, drug withdrawal ≤2
weeks; In the case of nitrosourea, mitomycin or monoclonal antibody, drug
withdrawal ≤6 weeks. If washout time is insufficient due to schedule or PK
characteristics of the drug, it needs to be discussed with the partner;
6. Patients with symptoms, disseminated to viscera, and risk of life-threatening
complications in a short period of time, patients with pleural effusion, peritoneal
effusion, and pericardial effusion who underwent puncture and drainage within three
weeks before the first administration;
7. Subjects with active or preexisting autoimmune diseases (e.g., systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid
disease, multiple sclerosis, vasculitis, glomerulonephritis, etc.) or those at high
risk (e.g., organ transplant recipients requiring immunosuppressive therapy). However,
subjects with the following conditions were allowed:
1. patients with type I diabetes who are stable on fixed doses of insulin;
2. autoimmune hypothyroidism with hormone replacement therapy only;
3. skin conditions requiring no systemic treatment (e.g. eczema, rashes covering
less than 10% of the body surface, psoriasis without eye symptoms, etc.);
4. patients who have resolved childhood asthma/allergy without intervention in
adulthood;
8. Cardiovascular disease within 6 months before screening meets any of the following
criteria:
1. congestive heart failure with New York Heart Association (NYHA) class Ⅱ or above;
Left ventricular ejection fraction (LVEF) < 50%;
2. severe arrhythmias requiring medical treatment;
3. QTcF (Fridericia's formula) > 450 msec in a man or > 470 msec in a woman, or the
presence of risk factors for torsdes pointes, such as hypokalemia, a family
history of long QT syndrome, or a family history of arrhythmias (e.g., the
Wolff-White syndrome), as judged by the investigator to be clinically
significant;
4. a history of myocardial infarction or severe/unstable angina within 6 months
before treatment;
5. a history of thromboembolic events of grade ≥3 within the past 2 years or
receiving thrombolytic or anticoagulant therapy due to a high risk of thrombosis;
9. Patients with sudden lung disease, interstitial lung disease or pneumonia, pulmonary
fibrosis, acute lung disease, etc. which could not be controlled after treatment,
except for local interstitial pneumonia induced by radiotherapy;
10. Uncontrolled systemic diseases, such as diabetes (fasting blood glucose ≥13.3mM),
hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100
mmHg), etc.;
11. Have a history of human immunodeficiency virus infection or other acquired or
congenital immunodeficiency diseases, or have a history of organ transplantation or
stem cell transplantation; Except for those who do not require immunosuppressive
therapy, such as corneal transplantation;
12. Evidence of active infection:
1. Hepatitis B (HBsAg positive, HBV-DNA≥500IU/ml and abnormal liver function);
2. Hepatitis C (HCV-Ab positive, HCV-RNA higher than the detection limit of
analytical method and abnormal liver function);
3. Systemic use of anti-infective agents for ≥7 days within 4 weeks before the first
dose or unexplained fever > 38.5°C during screening/before the first dose
(according to the investigator's judgment, fever caused by cancer could be
enrolled);
4. Patients with active pulmonary tuberculosis infection detected by medical history
or CT examination, or with a history of active pulmonary tuberculosis infection
within 1 year before enrollment, or with a history of active pulmonary
tuberculosis infection more than 1 year before enrollment but without regular
treatment;
13. A definite history of a previous neurological or mental disorder or a known history of
psychotropic substance abuse, alcohol abuse or drug use;
14. Received any investigational drug within 4 weeks before the first dose or was enrolled
in another clinical study (except if the patient was enrolled in an observational,
noninterventional clinical study or was in the follow-up period of an interventional
clinical study; or more than 5 half-lives of the last study medication);
15. Women who are pregnant or lactating, or who have a positive baseline pregnancy test;
16. Patients deemed by the investigator to be ineligible for inclusion in the study.
