Phase I clinical study to investigate the safety and tolerance of therapeutic BCG in postoperative adjuvant therapy in subjects with moderate to high-risk non-muscular invasive bladder cancer (NMIBC)

The purpose of this study was to evaluate the safety and tolerance, pharmacokinetic characteristics, ablative status, and immune response characteristics of the therapeutic BCG in postoperative adjuvant therapy in subjects with moderate and high-risk non-invasive bladder cancer (NMIBC).

The study consisted of three phases: screening period, administration observation period and safety follow-up period. subjects will be treated with 120 mg BCG.

Inclusion Criteria:

• Subjects were ≥18 years old and ≤85 years old, male or female;

• Subjects with non-myoinvasive bladder uroepithelial carcinoma initially diagnosed by histology [T1, Ta, or Tis stage (carcinoma in situ)] and assessed as moderate to high-risk non-myoinvasive bladder uroepithelial carcinoma requiring BCG injection adjuvant therapy according to the Guidelines for Bladder Cancer Diagnosis and Treatment (2022 edition); (Subjects considered for secondary resection may be included in the study after completion of secondary resection and pathology results confirm moderate or high risk non-myoinvasive bladder cancer);

• ECOG score: 0-2;

• Clinical laboratory tests meet the following characteristics:

  1. Blood routine: no hematopoietic growth factor or transfusion support was used within 14 days prior to enrollment, including: absolute neutrophil value (ANC) ≥1500/mm3 or ≥1.5×109/L; Platelets ≥100000/mm3 or 100×109/L; Hemoglobin ≥9 g/dL.
  2. Liver function: total serum bilirubin ≤1.5× upper limit of normal range (ULN), total serum bilirubin <3×ULN in subjects with Gilbert syndrome, aspartate and alanine aminotransferase (AST and ALT) ≤2.5×ULN.
  3. Renal function: defined as creatinine clearance ≥45 to 50 mL/min as estimated by the Cockcroft Gault formula.
  4. Coagulation function: Activated partial thromboplastin time (APTT) ≤1.5×ULN, International Normalized ratio (INR) ≤1.5×ULN

• The subjects voluntarily joined the study, signed the informed consent, had good compliance, and cooperated with follow-up.

Exclusion Criteria:

• Any of the following:

  1. Patients who are using immunosuppressive drugs, hormone drugs, or radiation therapy that the investigator has determined to be likely to cause systemic BCG disease reactions (patients who hormone injections for thyroid/adrenal resection may be included);
  2. Allergic to BCG vaccine or BCG products;
  3. Have active TB changes or are receiving anti-TB therapy;
  4. Known or suspected intraoperative perforation of the bladder; e Serious gross hematuria before administration was judged by the investigator, and the surgical wound was suspected to have not healed.

  f. The evaluators were judged to be associated with cystitis, or had previously received other bladder perfusion drugs, and were expected to have severe bladder irritation.

  f. Patients with a history of severe adverse reactions to BCG (BCG) sepsis or systemic infection; g. Complete bladder incontinence, defined as the use of six or more pads in a 24-hour period; h. Complete bladder incontinence, defined as the use of six or more pads in a 24-hour period;

• Combined with other genitourinary tumors or malignancies of other organs;

• Accompanied by serious diseases of cardiovascular and cerebrovascular, lung, liver, kidney and other important organs, or severe hypertension or diabetes that researchers judge can not be controlled clinically;

• Patients suffering from acute infectious diseases at the time of screening;

• Evidence of Myoinvasive locally advanced or metastatic urothelial carcinoma, or extrinsic non-Myoinvasive urothelial metastasized cell carcinoma, as determined by the investigator;

• Study participants who had received chemotherapy, radiation therapy, or anti-tumor immunotherapy within 4 weeks prior to treatment (except for immediate postoperative bladder infusion chemotherapy);

• Pregnant or lactating women;

• Subjects who are unable to use effective contraception during the trial period and within 3 months after the last dose;

• Participants who had participated in clinical trials of other therapeutic drugs within 1 month prior to enrollment;

• Known opioid or alcohol dependence;

• Human immunodeficiency virus (HIV) antibody, syphilis specific antibody positive, acute or chronic active hepatitis B (hepatitis B surface antigen (HBsAg) positive, and peripheral blood hepatitis B copy number ≥103/mL), hepatitis C virus (HCV) antibody positive (HCV copy number ≥10/mL);

• Patients with mental disorders or poor compliance as judged by the investigator;

• Any conditions that the investigator believes may increase risk to the subject or interfere with the execution of the clinical trial.