A Study of T3011 in Patients With BCG-Unresponsive High Risk NMIBC

Inclusion Criteria:

Participants may enter the study only if they meet all the following criteria:

1. Male or female, aged ≥18 years at the time of signing the ICF.

2. The participants will need to meet the following criteria:

3. Participants with a histologically confirmed diagnosis of NMIBC (Ta, T1 and/orCis).

4. During the study, the participants must voluntarily comply with thestudy-specified cystoscopy, urine cytology and randomized biopsy.

5. All toxicities caused by prior radiotherapy, chemotherapy or other treatments haverecovered to Grade ≤1 (CTCAE 5.0) (except for alopecia), including but not limitedto urinary tract infection, urinary tract irritation, and macroscopic hematuria;participants with Grade >1 anti-neoplastic treatment-related toxicities during thescreening period may be enrolled after discussion of the investigators and thesponsor.

6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.

7. Expected survival ≥24 weeks.

8. Laboratory test values meeting the following requirements :

1. Hematology ANC≥1.5×10^9/L. PLT count ≥75×10^9/L. Hemoglobin (HGB) ≥90 g/L. 2) Renalfunction Creatinine clearance ≥60 mL/min (based on Cockcroft-Gault equation forcalculation) 3) Hepatic function Serum total bilirubin (TBIL) ≤1.5×ULN. Aspertateaminotransferase (AST) and alanine transaminase (ALT) ≤2.5×ULN Serum ALB ≥30 g/L. 4)Coagulation function International normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN. Activated partial thromboplastin time (aPTT) ≤1.5×ULN. 7. For women ofchildbearing potential (WOCBP), the serum pregnancy test prior to the first dosemust be negative and the potential participant must promise to use medicallyacceptable and effective methods of contraception. after signing the ICF until atleast 6 months after the last dose.

8. Male participants of child-bearing potential must agree to use medically acceptableand effective methods of contraception after signing the ICF until at least 6 monthsafter the last dose; in addition, male potential participants must agree not todonate sperm during this period.

9. Participants who understand and voluntarily sign the written ICF, and are willingand able to comply with all trial requirements.

Exclusion Criteria:

Participants meeting any of the following criteria will not be allowed to participate in this study:

1. Participants meet the following criteria:

2. Concurrent or prior history of muscle-invasive (muscularis propria) or metastaticbladder cancer.

3. Urothelial carcinoma of the upper genitourinary tract or prostatic urethra within 24months prior to investigational product.

4. Having received chemotherapy, radiotherapy, biotherapy, endocrine therapy, targetedtherapy, immunotherapy, investigational product or other anti-neoplastic therapieswithin 4 weeks prior to investigational product.

5. Having received radiotherapy within 2 weeks prior to investigational product. 2.Planning to receive any anti-neoplastic therapy other than the investigationalproducts during this study.

6. A history of allergic reactions to HSV-1, IL-12, or anti-PD-1 antibodies orbiological components similar to them, or known allergic reactions to anycomponent of the T3011 formulation.

7. A history of brain metastasis or imaging-confirmed brain metastasis ,leptomeningeal disease, or spinal cord compression.

8. Concurrent or prior history of other malignancies than that treated in thisstudy.

9. History or evidence of high-risk cardiovascular diseases, including but notlimited to:

10. Serious cardiac rhythm or conduction abnormalities.

11. Acute myocardial infarction, unstable angina, or stroke, etc., developingwithin 6 months prior to the first dose of the investigational products.

12. Coronary angioplasty or stenting within 6 months prior to the first dose of theinvestigational products.

13. New York Heart Association (NYHA) criteria-defined cardiac function > Class II;echocardiogram-documented cardiac valve morphological abnormalities (Grade ≥2).

14. Left ventricular ejection fraction (LVEF) ˂lower limit of normal (LLN) of thestudy site, or ˂ 50% if no LLN is set at the site.

15. Poorly controlled blood pressure . 7. The following prior or concurrent immunedisorders that in the investigator's opinion would pose unpredictable risks tothe participants:

16. Immune-related pneumonia or other immune-related adverse reactions of Grade ≥3developing with prior immunotherapy (including but not limited to PD-1/PD-L1).

17. Concurrent active immune diseases requiring treatment with systemicimmunosuppressants (excluding autoimmune diseases not requiring interventionsuch as vitiligo and diseases treatable by other alternative drugs such ashypothyroidism that is treated with thyroid hormone replacement therapyoriginally), or concurrent immune diseases requiring treatment with systemicimmunosuppressants that have the potential to recurrence (e.g., systemic lupuserythematosus).

18. Other concurrent diseases requiring treatment with systemic immunosuppressants.

19. Unexplainable fever >38.5℃ during the screening or on the day of treatment (fever judged as tumor-induced by the investigator is eligible for enrollment)that in the investigator's opinion will affect the participation in this trialor interfere with the efficacy assessment.

20. The following persistent or active infections: human immunodeficiency virus (HIV) antibody-positive, hepatitis B (HBsAg-positive), hepatitis C (HCV-positive), and other active infections requiring systemic treatment.

21. Prior history of splenectomy or organ transplantation. 11. Having previouslyreceived treatment with oncolytic virus (e.g., T-VEC, T3011, CG0070).

22. Requiring oral or intravenous use of anti-herpes virus drugs, including but notlimited to acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir,foscarnet, and cidofovir (except for those to be used locally, such astopically), during the study.

23. Participants with known psychiatric disorders that may affect compliance intrial or with poor compliance.

24. Participants with a history of drug abuse (including "recreational use") orsubstance abuse (including alcohol) within one year prior to signing ICF.

25. Being pregnant or breast feeding, or planning to become pregnant or give birthduring this trial.

26. Having received any live attenuated vaccine within 4 weeks prior toinvestigational product or planning to receive such vaccines during the study.

27. Having undergone a major surgery. 18. Any diseases that at the investigator'sdiscretion may confound the trial results, interfere with the participation inthe entire trial, and/or would make participating in the trial not in theparticipant's best interest, or a medical history with treatment or laboratoryabnormalities, or any other circumstances that would make it inappropriate forthe participant to be enrolled.