Evaluating the Safety and Efficacy of BioTTT001 in Patients With Recurrent/Progressive High-grade Glioma.

A Phase Ib/Ⅱ Clinical Study to Evaluate the Safety, Tolerability, Biodistribution Characteristics and Preliminary Efficacy of Recombinant Human nsIL12 Oncolytic Adenovirus Injection With Recurrent/Progressive High-grade Glioma.

This study is a single-arm, open-label, dose-escalation and dose-expanding Phase Ⅰb/Ⅱ clinical study to evaluate the safety, tolerability, biodistribution characteristics and preliminary efficacy of recombinant human nsIL12 oncolytic adenovirus injection (BioTTT001) in patients with recurrent/progressive high-grade glioma.

Phase Ⅰb Dose Escalation Study:Three dose groups were established in the dose escalation phase, namely 1.0×10^10 VP, 5.0×10^10 VP and 2.5×10^11 VP. The traditional "3+3" dose escalation method was used for dose escalation, with at least 3 subjects enrolled in each dose group, and each subject received only one corresponding dose until the MTD and/or RP2D were determined.It is planned to enroll 12~18 subjects, and the final sample size of enrollment depends on the number of DLT, the number of dose groups that are escalated before the DLT is observed, and the determination of the MTD.

Phase Ⅱ Dose Expansion Study:In this phase, one dose group was selected for a dose expansion study to further evaluate the efficacy and safety of BioTTT001 in patients with recurrent/progressive high-grade glioma.It is planned to select 1 dosage that may be used for phase Ⅰ clinical research to expand enrollment, and it is planned to enroll 10~30 subjects.

Inclusion Criteria:

1. Aged 18 years or older, both male and female are eligible;
2. Patients with high-grade glioma who have recurred/progressed after receiving standard therapy as confirmed by histopathological confirmation meeting the 2021 World Health Organization (WHO) classification criteria for central nervous system tumors;
3. Karnofsky Performance Score (KPS) ≥ 60 points (see Appendix 2);
4. Suitable for placement of Ommaya sac as judged by the investigator to be eligible for administration;
5. Estimated survival ≥ 3 months;
6. Good organ function;
7. Voluntary participation and ability to sign informed consent form prior to the start of study-related procedures, after explaining the content of the study;
8. Subjects of childbearing potential and sexually active partners must be willing to use a medically approved and effective method of contraception, such as a double-barrier method of contraception, during treatment and for 6 months after the last dose, and the male agrees not to donate sperm;
9. Females of childbearing potential, must have a negative blood pregnancy test result within 7 days prior to the first dose and be willing to undergo additional pregnancy tests during the study. Females of childbearing potential who have not undergone surgical sterilization (i.e., bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) or are not postmenopausal; Menopause is the absence of menopause for 12 months in women over ≥ age of 45 and the exclusion of other causes of amenorrhea. In addition, serum follicle-stimulating hormone (FSH) levels in women under 50 years of age must be in the postmenopausal range for menopause to be confirmed;
10. Good compliance, willing and able to follow all research procedures, and cooperate with observation and follow-up.

Exclusion Criteria:

1. Received anti-tumor drug therapy such as radiotherapy, chemotherapy, biological therapy, endocrine therapy, targeted therapy and other anti-tumor drugs within 4 weeks before the first dose (excluding immunotherapy, nitrosourea, mitomycin C, oral fluorouracil, small molecule targeted drugs, and traditional Chinese medicines with anti-tumor indications);
2. Treatment with any other unmarketed investigational drug within 4 weeks prior to the first dose;
3. Surgical surgery of major organs within 4 weeks prior to the first dose (excluding live puncture) or have had significant trauma, or need to undergo elective surgery during the study;
4. Those who have a history of cell therapy, gene therapy, and oncolytic virus therapy in the past;
5. Those who have known or suspected hypersensitivity to the active ingredients of the study drug, excipients, and imaging contrast agents;
6. Those who have a history of organ transplantation or plan to undergo organ transplantation during the study;
7. Patients with active infection or uncontrollable infection requiring intravenous systemic therapy, or fever of unknown cause > 38.5°C during the screening period and before the first dose;
8. Accompanied by severe coagulation disorder or other evidence of obvious bleeding risk; history of gastrointestinal bleeding; Any other ≥ CTCAE grade 2 bleeding event within the past 6 months;
9. Subjects who have received systemic corticosteroids (>10 mg/day of prednisone or equivalent) or other immunosuppressants within 14 days prior to the first dose; except in the following cases: use of topical, ocular, intra-articular, intranasal, and inhaled corticosteroid treatments; short-term use of corticosteroids for prophylactic treatment (e.g., prevention of contrast agent allergy);
10. Adverse reactions from previous anti-tumor treatments have not yet recovered to ≤ Grade 1 according to CTCAE 5.0 (except for toxicities deemed to pose no safety risk by the investigator, such as hair loss, Grade 2 peripheral neuropathy, etc.);
11. History of immunodeficiency, including positive HIV antibody test;
12. Active hepatitis B (HBsAg positive and HBV-DNA > 500 IU/ml or lower limit of detection at the study center [only if the study center's detection limit is higher than 500 IU/ml]); active hepatitis C (HCV antibody positive and HCV-RNA > the detection limit at the study center), positive treponema pallidum antibody for syphilis;
13. Hypertension poorly controlled as judged by the investigator (arterial hypertension not controlled despite standard treatment: systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg);
14. History of severe cardiovascular disease, such as: ventricular arrhythmia requiring clinical intervention; QTc interval >480 ms; acute coronary syndrome, congestive heart failure, stroke, or other grade III or higher cardiovascular events within 6 months prior to first administration; New York Heart Association (NYHA) functional class ≥II (see Appendix 4) or left ventricular ejection fraction (LVEF) <50%;
15. Presence of other untreated malignancies within the past 3 years or currently, except for carcinoma in situ that is considered clinically curable, such as in situ cervical cancer and basal cell carcinoma;
16. Active or past autoimmune diseases with potential for recurrence (including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except clinically stable autoimmune thyroiditis;
17. Received live attenuated or recombinant vaccines within 4 weeks before first administration, or received inactivated vaccines within 2 weeks before first administration;
18. Previous immunotherapy with immune-related adverse events (irAE) of grade ≥3;
19. Tumorous lesions in the brainstem, cerebellum, posterior cranial fossa, or spinal cord, or presence of leptomeningeal disease;
20. Diffuse subependymal and subarachnoid space disease;
21. Patients whose lesions are closely related to the ventricles, posing a risk of intraventricular dissemination (patients judged by the investigator that the oncolytic virus cannot directly reach the ventricles after administration may be included);
22. History of encephalitis, multiple sclerosis, or other central nervous system infections;
23. Patients with brain herniation syndrome;
24. Known alcohol or drug dependence;
25. Patients with psychiatric disorders or poor compliance;
26. Pregnant or breastfeeding women;
27. Participants who, in the opinion of the investigator, have other serious systemic diseases or other reasons that make them unsuitable for participation in this clinical study.