A Study to Evaluate the Efficacy and Safety of RAG-01 as Monotherapy and in Combination With Chemotherapy in Patients With Non-muscle Invasive Bladder Cancer (NMIBC).

A Randomized, Controlled, Multicenter Clinical Study to Evaluate the Efficacy and Safety of RAG-01 Monotherapy and RAG-01 in Combination With Chemotherapy in Intermediate/High-risk Patients With Non-muscle Invasive Bladder Cancer (NMIBC).

This is a randomized, controlled, multicenter clinical study to evaluate the efficacy and safety of RAG-01 monotherapy and in combination with chemotherapy in patients with NMIBC.

Inclusion Criteria:

1. Voluntarily agrees to participate in this study and provides written informed consent prior to the initiation of any study-specific procedures.

2. Is aged ≥18 years at the time of signing the informed consent form (ICF).

3. Has histologically confirmed tumor tissue obtained within 12 weeks prior to the first study treatment, with urothelial carcinoma as the predominant histologic subtype (≥90%), and is classified according to the American Urological Association (AUA) guidelines as follows:

   • Cohort A: high-risk non-muscle-invasive bladder cancer (NMIBC).
   • Cohort B: intermediate-risk NMIBC.

4. Regardless of prior bacillus Calmette-Guérin (BCG) treatment, is confirmed before enrollment to be BCG-intolerant, ineligible for BCG, unwilling to receive BCG, or unable to access BCG treatment for any reason.

5. Has no resectable lesion, as confirmed by cystoscopy and/or transurethral resection of bladder tumor (TURBT), within 12 weeks prior to the first administration of study treatment.

6. Is willing to provide pathological tissue specimens.

7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.

8. Has adequate hematologic and organ function within 14 days prior to enrollment.

9. Female participants must agree to use effective contraception during treatment or be surgically sterile or postmenopausal. Women of childbearing potential must have a negative pregnancy test during the screening period; however, pregnancy testing is also required for participants with bilateral tubal ligation. Male participants must be surgically sterile or agree to use effective contraception during treatment. Participants must use contraception from the time of signing the ICF until 3 months after completion of study treatment. The definition of effective contraception will be based on the investigator's judgment.

Exclusion Criteria:

1. Low-risk NMIBC.
2. Very high-risk NMIBC.
3. Tumors staged as T2 or higher, or urothelial carcinoma of the upper urinary tract or urethra (renal pelvis, ureter, or urethra).
4. Predominantly non-urothelial histology, including squamous cell carcinoma, adenocarcinoma, or other non-urothelial carcinomas.
5. Receipt of antitumor intravesical therapy between the most recent transurethral resection of bladder tumor (TURBT) and the first administration of study treatment, except for a single immediate postoperative intravesical chemotherapy instillation.
6. Receipt of any antitumor therapy within 4 weeks prior to the first administration of study treatment.
7. Participation in another clinical trial involving an antitumor investigational drug within 4 weeks prior to the first administration of study treatment.
8. Prior treatment with small nucleic acid-based antitumor agents, p21-targeted antitumor agents, or cyclin-dependent kinase (CDK) inhibitors.
9. Major surgery within 4 weeks prior to signing the informed consent form (ICF).
10. History of malignancy within 2 years prior to enrollment, except for curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix; or ongoing requirement for antitumor therapy.
11. Any Grade ≥3 hemorrhage, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 6.0, at any site within 6 weeks prior to enrollment, regardless of whether the event has resolved.
12. Chronic renal injury or inflammation, or renal injury or inflammation not recovered to Grade ≤1 according to NCI CTCAE version 6.0.
13. Any of the following within 6 months prior to enrollment: myocardial infarction; severe or unstable angina; coronary or peripheral arterial bypass grafting; symptomatic congestive heart failure; cerebrovascular accident or transient ischemic attack; or pulmonary embolism.
14. Uncontrolled hypertension.
15. New York Heart Association (NYHA) Class III or IV heart failure, or left ventricular ejection fraction (LVEF) <50%.
16. Prolonged corrected QT (QTc) interval.
17. Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or tuberculosis at screening, including HIV antibody positivity; hepatitis B surface antigen (HBsAg) positivity with detectable HBV DNA; or HCV antibody positivity with detectable HCV RNA.
18. Severe infection within 4 weeks prior to the first administration of study treatment, or active infection of Grade ≥2 per CTCAE requiring systemic antibiotic treatment within 1 week prior to the first administration of study treatment.
19. Intolerance of or inability to receive intravesical instillation, or inability to retain intravesical study treatment for the duration required by the protocol for any reason.
20. Anuria, urinary incontinence, or urinary tract obstruction within 4 weeks prior to enrollment.
21. Persistent gross hematuria despite treatment within 1 week prior to enrollment.
22. Uncontrolled pleural effusion, pericardial effusion, or ascites.
23. Severe pulmonary disease of significant clinical relevance.
24. Confirmed vesicoureteral reflux or bladder perforation.
25. Any other serious acute or chronic medical condition that, in the investigator's judgment, may increase the risk associated with study participation or study treatment, or may interfere with the interpretation or assessment of study results.
26. Severe psychological or psychiatric disorder that, in the investigator's judgment, is likely to result in inadequate compliance with study requirements.