BCG for Therapeutic Use Phase Ⅲ Clinical Trial

Research topic: A randomized, double-blind, active-controlled, multicenter phase III clinical trial evaluating the efficacy and safety of therapeutic BCG for the prevention of postoperative recurrence of non-muscle-invasive bladder cancer in people aged 18 years and older.

Study endpoints: Endpoint efficacy: Main efficacy measures: 1-year recurrence-free survival rate (1-year RFS%): To assess the proportion of participants who are relapse-free or die from randomization up to 1 year, whichever occurs first. Secondary efficacy endpoint: 2-year recurrence-free survival rate (2-year RFS%): Assessing the proportion of subjects who have not experienced recurrence or death (whichever occurs first) from randomization until 2 years. 1-year progression-free survival rate (1-year PFS%): Assessing the proportion of subjects experiencing tumor progression or death from randomization until 1 year. The 2-year progression-free survival rate (2-year PFS%) assesses the proportion of subjects experiencing tumor progression or death from the time of randomization until 2 years. Security endpoint: Incidence of all AEs and SAEs; Any clinically significant abnormalities in vital signs or physical examinations during the trial period; Any clinically significant abnormalities found during the trial period laboratory examinations or electrocardiogram examinations. Other destinations: Changes in the levels of interleukin 2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-12 (IL-12), interferon γ (IFN-γ), and tumor necrosis factor (TNF) in urine excreted at 4 h±1 h, 8 h±, 2 h, and 24 h±3 h after the 1st (V1), 6th (V6), 9th (V9), and 10th (V10) administration.

Overall design: This study adopts a randomized, double-blind, positive-controlled, multicenter trial design, including three phases: screening, treatment, and follow-up. A total of 438 subjects will be enrolled in this study, with a 1:1 random allocation to the experimental group and the control group, both consisting of 219 subjects. Stratification will be based on baseline risk level (high risk/medium risk) and whether urine PD samples are collected (yes/no). Selection period: During the first 28 days prior to administration, the subjects will undergo eligibility confirmation for enrollment. Subjects who meet the eligibility criteria will enter the treatment phase and receive the investigational drug infusion.

Treatment period (Year 1): The treatment period includes the induction phase, consolidation phase, and maintenance phase.

After undergoing transurethral bladder tumor resection, eligible subjects are screened and randomly assigned to the study. Within 2 to 12 weeks after surgery, subjects receive bladder instillation therapy: once a week during the induction phase for a total of 6 times, once every two weeks during the consolidation phase for a total of 3 times, and once every 4 weeks during the maintenance phase for a total of 19 times, continuing until 1 year after surgery.

During the first year of the study, subjects undergo imaging examinations every 12 months, urine cytology examinations every 3 months, and cystoscopy. If a subject shows positive results in either cystoscopy or urine cytology, the researcher may decide to perform additional imaging examinations.

Early Termination of Treatment Visit: For subjects who discontinue treatment early without completing the first year of infusion therapy in the treatment period and without experiencing tumor recurrence or progression, an Early Termination of Treatment Visit will be conducted within 30 days after the last dose. If subsequent other local or systemic anti-tumor therapies are received, this should be accurately recorded.

Follow-up period (Year 2): After completing the first year of infusion therapy in the treatment period, or for subjects who discontinued treatment early without tumor recurrence or progression, or subjects who continue receiving treatment into the second year, follow-up will be conducted during the second year of the study. All subjects meeting the above conditions will undergo imaging examinations every 12 months, and urine cytology examinations and cystoscopy every 3 months, until the subject experiences tumor recurrence or progression, withdraws informed consent, is lost to follow-up, the sponsor terminates the study, or death occurs (whichever occurs first). If a subject has a positive result in either cystoscopy or urine cytology, the investigator may decide to perform additional imaging examinations.

This trial plans to conduct the first analysis of the efficacy and safety of the investigational product after all subjects have experienced recurrence or death, or have completed one year of follow-up observation. The first analysis will involve unblinding and statistical analysis performed by a firewalled unblinded team, while the main study team will remain blinded at the individual subject level to continue follow-up of trial subjects. The final unblinding and statistical analysis will be conducted upon completion of the entire trial.

Inclusion criteria

• 1. Age≥ 18 years old, male or female;
• 2. According to the Guidelines for the Diagnosis and Treatment of Bladder Cancer (2022 Edition), the initial histological diagnosis of intermediate- and high-risk non-muscle-invasive urothelial carcinoma of the bladder (T1, Ta or Tis) and the need for BCG bladder infusion adjuvant therapy is evaluated;
• 3. Patients undergoing transurethral bladder tumor resection need to meet the requirements of all tumors to have no visible tumors after surgery. This study can also enroll patients who need a second electroresection, subjects who meet the secondary electroresection criteria are recommended to undergo secondary electroresection and should be included in the study after comprehensive evaluation based on the two pathological results (BCG perfusion for treatment should be carried out within 2~12 weeks after surgery, cystoscopy should be added more than 4 weeks after surgery to ensure that there is no visible tumor after surgery, and the subjects who underwent secondary resection should be calculated based on the postoperative time of the second electroresection); Note: The criteria for the second resection: (1) the first TURBt is insufficient; (2) the first electrosection of non-myometrial tissue specimens; (3) T1 tumors; (4) High-grade (G3) tumors, except for carcinoma in situ. The second resection is recommended to be performed within 2-6 weeks after the first resection, and no other perfusion therapy is allowed except for the bladder infusion chemotherapy drugs immediately after the first and second resection;
• 4. Eastern Cooperative Oncology Group (ECOG) score (see Appendix 1 for details): 0~2 points;
• 5. At screening, clinical laboratory tests meet the following characteristics:

• Blood routine: no use of hematopoietic growth factors or blood transfusion support within 14 days before randomization, including: absolute neutrophil count (ANC) ≥1500/mm^3 or ≥1.5×10^9/L; Platelets≥ 100000/mm^3 or 100×10^9/L; Hemoglobin ≥ 9 g/dL.
• Liver function: total bilirubin ≤ 1.5× upper limit of normal range (ULN), subjects with Gilbert's syndrome require total bilirubin <3×ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN.
• Renal function: defined as creatinine clearance estimated according to the Cockcroft Gault formula (Appendix 2) ≥ 30mL/min;
• Coagulation function: activated partial thromboplastin time (APTT) ≤ 1.5×ULN, and the international normalized ratio (INR) ≤ 1.5×ULN.
• 6. Voluntarily participate in this trial, with full informed consent and signed written informed consent.

Exclusion criteria

• 1. Those who have immunodeficiency or damage (such as AIDS patients), are using immunosuppressive drugs, steroid hormones, etc., which may cause systemic BCG disease reaction (other hormones such as patients who are given corresponding hormone therapy after thyroid/adrenal resection can be enrolled);
• 2. Those who are allergic to BCG and its excipients;
• 3. Active tuberculosis, those who are receiving or have received anti-tuberculosis treatment within 6 months before screening;
• 4. Patients with severe cardiovascular and cerebrovascular, liver, lung, and kidney diseases at the time of screening;
• 5. Patients with urothelial carcinoma or other urogenital tumors or other organ tumors in any part outside the bladder during screening, and no obvious tumor recurrence or progression in the past 3 years, and stable condition can be considered for inclusion, such as basal cell or squamous cell skin cancer that has been adequately treated; carcinoma in situ of the breast or cervix; Low-grade prostate cancer that is monitored without any planned therapeutic intervention (e.g., surgery, radiotherapy, or castration); and other concurrent malignancies that in the opinion of the investigator have a very low likelihood of progression;
• 6. Patients with histologically confirmed muscle-invasive, locally advanced, unresectable or metastatic urothelial carcinoma or a history of this disease (i.e., ≥ T2);
• 7. Those who have received any BCG treatment for NMIBC in the past;
• 8. Those who know or suspect that abnormal conditions such as bladder perforation occur during surgery;
• 9. Those who suspect that the surgical wound has not healed or the urinary tract mucosa is damaged;
• 10. Those who have been assessed by the investigator to be accompanied by cystitis (such as urinary frequency, urgency, dysuria, etc.), or have received other bladder infusion drugs and have severe bladder irritation, which is expected to affect the evaluation of this study;
• 11. In addition to immediate postoperative intravesical chemotherapy, patients who have received other systemic anti-tumor treatments such as chemotherapy, radiotherapy, and immunotherapy for the disease under study;
• 12. Pregnant or lactating women;
• 13. Those who cannot guarantee effective contraception during the trial period to 6 months after the last dose;
• 14. Received treatment with other clinical trial drugs (except placebo) or clinical trial devices within 3 months before the first dose;
• 15. Those who have a history of alcoholism, drug abuse or drug abuse within 6 months before screening;
• 16. Presence of any of the following: positive human immunodeficiency virus (HIV) antibody, positive syphilis-specific antibody, active hepatitis B (hepatitis B surface antigen (HBsAg) positive and hepatitis B virus deoxyribonucleic acid (DNA) copy number ≥200 IU/mL or 1000 copies/mL), hepatitis C virus (HCV) antibody positive and HCV virus copy number higher than the upper limit of normal in the research center≥ 10^3/mL;
• 17. Any condition that, in the opinion of the investigator, may increase the risk of the subject or interfere with the performance of the clinical trial.