A Phase I-II Study of Novel Oncolytic Virus VG161 via Intravesical Instillation for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer (VG-INFUSE Trial)

Background: The treatment of recurrent/refractory non-muscle-invasive bladder cancer (NMIBC), particularly BCG-unresponsive disease, remains a significant clinical challenge. Oncolytic virotherapy represents a promising novel therapeutic strategy. This study aims to evaluate the safety, preliminary efficacy, and biological activity of VG161, a novel oncolytic virus, administered via intravesical instillation.

Methods: This is a single-arm, prospective Phase I-II clinical trial conducted at Fudan University Shanghai Cancer Center, led by Drs. Zhang Hailiang and Ye Dingwei. Over an estimated duration of 2 years, 8 to 24 patients with recurrent/refractory NMIBC will be enrolled. The primary objectives are to assess the safety profile, identify the maximum tolerated dose (MTD), and determine the recommended Phase II dose (RP2D) of intravesical VG161. Preliminary efficacy will be evaluated based on recurrence-free survival (RFS) per RECIST 1.1. Key secondary and exploratory objectives include characterizing the pharmacokinetics (PK) and viral shedding profile in urine and blood; investigating pharmacodynamic immune responses and potential predictive biomarkers (e.g., via high-throughput sequencing of the tumor microenvironment, CyTOF, and multiplex immunohistochemistry); and analyzing dynamic changes in peripheral immune cell phenotypes and circulating tumor DNA (ctDNA).

Expected Outcomes: This trial will define the safety, tolerability, and preliminary clinical activity of intravesical VG161. Furthermore, it will provide crucial insights into its PK profile, mechanism of action, and correlative biomarkers, which will inform subsequent clinical development for BCG-unresponsive bladder cancer.

Inclusion Criteria:

Subjects must meet all of the following criteria for enrollment:

1. Willing and able to provide written informed consent and to comply with the protocol.

2. Age ≥ 18 years.

3. Histologically or cytologically confirmed urothelial carcinoma of the bladder.

4. Cystoscopically and pathologically (via biopsy) confirmed recurrence of non-muscle-invasive bladder cancer, with ≥ 3 prior recurrences.

5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

6. Life expectancy ≥ 3 months.

7. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment, defined as follows:

   Hematologic (without transfusion or growth factor support within 14 days): Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelets (PLT) ≥ 75 × 10⁹/L; Hemoglobin (Hb) ≥ 90 g/L.

   Hepatic: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN for patients with known liver metastases).

   Renal: Serum creatinine (Cr) ≤ 1.5 × ULN and calculated creatinine clearance ≥ 50 mL/min (using the Cockcroft-Gault formula).

   Coagulation: Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; Prothrombin time (PT) ≤ 1.5 × ULN; International normalized ratio (INR) ≤ 1.5 × ULN.

8. For women of childbearing potential: negative serum or urine pregnancy test within 7 days prior to study entry, agreement to use effective contraception (e.g., intrauterine device, contraceptive pills, or condoms) during the study and for 6 months after the last dose, and must be non-lactating. For men: agreement to use effective contraception during the study and for 6 months after the last dose.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Pregnant or lactating women.

2. Major surgical procedure within 4 weeks prior to the first dose of the study drug, or anticipation of the need for a major surgical procedure (other than for diagnostic purposes) during the study.

3. Prior anti-tumor therapy (including but not limited to chemotherapy, radiotherapy, biotherapy, endocrine therapy, targeted therapy, immunotherapy) within 4 weeks prior to the first dose of the study drug, with the following exceptions:

   Nitrosoureas or mitomycin C within 6 weeks prior.

   Oral fluoropyrimidines and small-molecule targeted agents within 2 weeks prior or within 5 half-lives of the drug (whichever is longer).

   Traditional Chinese medicine with approved anti-tumor indications within 2 weeks prior.

4. Treatment with systemic corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive agents within 14 days prior to the first dose. The following are allowed: use of topical, ocular, intra-articular, intranasal, or inhaled corticosteroids; short-term prophylactic use of corticosteroids (e.g., for contrast allergy prevention).

5. Administration of a live, attenuated vaccine within 4 weeks prior to the first dose, or anticipation that such a vaccine will be required during the study.

6. Severe infection within 4 weeks prior to the first dose, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

7. Significant cardiovascular disease, such as New York Heart Association Class II or greater heart disease, myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina.

8. Patients with uncontrolled type 1 diabetes mellitus. Patients with type 1 diabetes on a stable insulin regimen are eligible.

9. Active hepatitis infection (defined as positive hepatitis B surface antigen [HBsAg] at screening) or hepatitis C. Patients with past or resolved HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody [anti-HBc]) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

10. Evidence of significant uncontrolled concurrent illness that could affect compliance with the protocol or interpretation of results, including significant liver disease, positive HIV test, active tuberculosis, or a history of gastrointestinal conditions (medical or extensive surgery) that may interfere with drug absorption.

11. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

12. Known immediate or delayed hypersensitivity, intolerance, or contraindication to any component of the novel oncolytic virus formulation.

13. Negative test results for both Type 1 Herpes Simplex Virus IgG and IgM antibodies.

14. Active recurrent herpes simplex virus infection with corresponding clinical manifestations (e.g., herpes labialis, herpes keratitis, herpes dermatitis, genital herpes) at the time of screening.