This is a prospective, open label, single center clinical study on the use of recombinant human adenovirus type 5 injection for bladder instillation therapy in high-risk non muscle invasive bladder urothelial carcinoma patients. The study was administered in a dose escalation manner, starting from a relatively safe dose of 1.0 × 10 \^ 12vp as the first dose group, and a 6-week DLT observation period was set up to ensure the safety of the study. Expected to enroll 12-18 participants. The subjects need to undergo maximum transurethral resection of the bladder (TURBT) and imaging diagnosis, and biological samples such as blood, urine, and biopsy tissue should be collected before treatment. The patient will receive bladder instillation therapy with recombinant human adenovirus type 5 injection after TURBT surgery. The subjects should receive a fixed dose of recombinant human adenovirus type 5 injection (1.0 × 10 \^ 12 vp or 2.0 × 10 \^ 12 vp or 3.0 × 10 \^ 12 vp) per week via bladder instillation for 6 weeks for induction therapy, followed by maintenance infusion of the same dose once a week for 3 weeks after the first induction infusion at 3, 6, 12, 18, and 24 months. After the first intravesical intervention for 3 months, tumor site pathology, imaging, and cytology will be obtained through diagnostic TURBT for tumor evaluation. Patients who achieve complete remission will maintain the same induction cycle, and will receive follow-up every 3 months for 2 years, every 6 months for more than 2 years, and once a year for more than 3 years. Patients who are intolerant to intravesical treatment (evaluated by the researchers) will be directly discontinued.
Voluntarily participate in this clinical study, understand the study procedures, and provide written informed consent.
Aged ≥18 years, regardless of gender.
Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.
Expected survival time ≥2 years.
Prior Bladder Radiotherapy
Prior Treatments Without Disease Progression (as Assessed by Investigator)
Previous intravesical therapy with cytotoxic chemotherapy or other agents (e.g., oncolytic viruses, IL-2).
Systemic chemotherapy, immune checkpoint inhibitors, or antibody-drug conjugates (ADCs).
Single group
Recombinant Human Adenovirus Type 5 injection
DrugThe administration cycle of this experiment includes 6 induction perfusion periods (once a week for 6 consecutive weeks) and 15 maintenance perfusion periods (once a week for the first 3 weeks after 3, 6, 12, 18, and 24 months of initial induction perfusion, for a total of 3 times a month). This study will adopt the "3+3" principle for dose escalation until DLT is determined. The DLT observation period is 6 weeks before the induction perfusion period. This experiment will preset three dose groups: 1 × 10\^12vp, 2 × 10\^12vp, and 3 × 10\^12vp.
3-month CR
Complete response (CR) rate of patients receiving bladder instillation of recombinant human adenovirus type 5 injection at 3 months in each dose group.CR is defined as negative urine cytology examination, no tumor detected on imaging, and negative biopsy in the ITT population. Subjects with no response data in the primary analysis population (FAS) will be counted as non responders. Analyze based on the effectiveness analysis set
DLT
DLT is defined as any of the following events related to the study drug that occur during the DLT observation period (grading criteria refer to NCI CTCAE 5.0): 1. Hematological toxicity: * Grade 4 neutrophil count decrease lasting\>5 days; -≥ Grade 3 febrile neutropenia; * Grade 4 anemia; * Grade 4 platelet count decreased; * Grade 3 platelet count decrease lasting\>7 days; * Grade 3 platelet count decrease accompanied by significant clinical bleeding symptoms; * The decrease in lymphocyte count at level 4 lasts for ≥ 14 days. 2. Liver toxicity: * Level 4 ALT or AST elevation; * Level 3 ALT or AST elevation accompanied by ≥ level 2 TBIL elevation; 3. Urinary tract related adverse reactions: -Bladder perforation or urinary fistula; -≥ grade 3 urinary tract infection, bladder spasm, cystitis, hematuria, urinary retention, urinary pain, urinary incontinnence, and lasted for\>7 days after symptomatic treatment. 4. Other non hematological toxicities: * Other non hematological toxicities of grade ≥ 3.
MTD
This study will adopt dose escalation, starting from the initial dose group, with at least 3 cases in each dose group. If no DLT occurs, it will be raised to the next dose group; If one case of DLT occurs, three cases will be re enrolled in the same dose group. If the three newly enrolled cases do not have DLT, they will be promoted to the next dose group. Otherwise, the dose escalation experiment will be stopped. This dose level is the MTD
AEs
The types, incidence, severity (rated according to CTCAE v5.0), duration, and correlation with the investigational drug of adverse events (AEs) and serious adverse events (SAEs), including vital signs, abnormal electrocardiograms, and laboratory tests;
DoR
Duration of CR remission
6-month CR
12-month CR
Biomarkers
Biomarkers of tissue, blood, and urine, including but not limited to CCF, CNA, and other parameters of utDNA, before and during the infusion of recombinant human adenovirus type 5 injection
Drug Recovery in Instillation Fluid and Urine
PK parameter
Pharmacokinetic parameters including plasma drug concentration , etc.
PD parameter
Including but not limited to levels of cytokines such as interleukin-6 (IL-6) and interferon-I (IFN-I) in urine
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