A Study of RAG-01 in Patients With Non-muscle-invasive Bladder Cancer (NMIBC) Who Have Failed Bacillus Calmette Guérin (BCG) Therapy

This study includes a dose escalation and a dose expansion. The dose escalation part will adopt a '3+3' dose escalation design. Additional subjects may be enrolled to have approximately 12 patients in each selected dose level for RDE determination. A randomized, open label, parallel-arm study will be conducted during the dose expansion part for further dose exploration. Approximately 40-60 subjects will be randomized in a 1:1 ratio into two treatment groups with dose levels selected from dose escalation part of the study. Randomization will be stratified based on disease type at enrollment (papillary-only vs. CIS). A dose selection analysis will be performed to assess safety, efficacy, PK, and PD, where applicable, to determine the optimal dose for RAG-01. The main study period includes the screening, initial treatment and DLT assessment period, second and third treatment period and the sequential follow-up period.

Inclusion criteria

• Ability to understand the study and have signed the informed consent form;
• Any adult ≥ 18 years old;
• Pathologically confirmed high grade NMIBC defined as grade 2 or grade 3 disease;
• Expected survival ≥ 6 months;
• ECOG PS ≤2;
• Sufficient organ functions, as defined below:

Investigations Hematology Absolute Neutrophil Count (ANC): ≥ 1.5 x 109/L Hemoglobin: ≥ 90 g/L Platelet: ≥ 100 x 109/L Liver Function Serum bilirubin: ≤ 1.25×ULN or 2.5×ULN（with Gilbert syndrome） AST & ALT: ≤ 2.5×ULN Renal Function Creatinine Clearance (Cockcroft-Gault equation): ≥ 30 mL/min

• Subject must be able to tolerate catheterization;
• Female subject of childbearing potential and her spouse must use adopt effective contraception (non-pharmacological contraception required) from signing informed consent to within 6 months after the last instillation;

Exclusion criteria

• Subject who is allergy to RAG-01 or similar products;
• Except for TURBT, the subject received other anti-tumor treatments, and the last administration date is within ≤ 21 days or 5 half-lifes whichever is shorter from the date of signing ICF;
• Subject with imaging examination diagnosed extravesical metastasis, including ureter and urethra;
• Subject has other malignancies within the past 3 years, except for adequately treated carcinoma of the cervix, basal or squamous cell carcinomas of the skin, or adenocarcinoma of the prostate that has been surgically treated with a post-treatment PSA that is non-detectable;
• The following illnesses have not been relieved to CTCAE 0-1:

• Uncontrolled acute and chronic infections, such as pneumonia, biliary tract infection, hepatitis B virus infection and hepatitis C virus infection;
• Dyspnea;
• Acute and chronic kidney injury, and inflammation;
• Urinary incontinence;
• Urinary frequency;
• Urinary tract obstruction (except benign prostatic hypertrophy);
• Subject could not hold the urine for at least 90 mins due to any reason;
• New York Heart Association (NYHA) 3 or 4 grade;
• Coronary heart disease related symptoms have not been relieved to CTCAE 0-1, including: myocardial infarction, unstable angina pectoris, congestive heart failure and arrhythmia;
• Subject with QTc >470 msec.
• Cerebrovascular accidents have not been relieved to CTCAE 0-1;
• HIV positive; Active hepatitis B or C. For active HBV, it's defined as HBsAg positive with HBV DNA ≥ ULN, for active HCV, it's defined as HCV antibody positive with HCV RNA ≥ ULN, respectively.
• Subject is pregnant or lactating during the treatment period;
• History of central nervous system or psychiatric disorders, e.g., epilepsy or dementia;
• Other severe systemic diseases which might compromise the subject's compliance to the study, e.g., uncontrolled diabetes, gastrointestinal disorders, and renal diseases;
• Any other situations which are judged by the investigator, would exposure the subject to unnecessary risk, therefore he/she is not eligible.