A Clinical Study Evaluating the Safety, Tolerability, and Preliminary Efficacy of Recombinant Oncolytic Adenovirus Injection (KD01) Via Intravesical Instillation in Bladder Cancer (BC)
Recombinant oncolytic adenovirus injection (KD01) is an oncolytic virus product. Its main component is a conditionally replicative recombinant human type 5 adenovirus, where part of the E3 region has been replaced with the gene encoding the tBid apoptotic protein.AK104 is a humanized bispecific antibody co-targeting PD-1 (Programmed Cell Death Protein 1) and CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4)-two key immune checkpoint receptors. It is designed as a novel tetrameric construct that preferentially binds to tumor-infiltrating lymphocytes (TILs) co-expressing PD-1 and CTLA-4 in the tumor microenvironment (with higher avidity than in peripheral tissues).This is a Phase I clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of intravesical instillation of recombinant oncolytic adenovirus injection (KD01) in patients with bladder cancer.This study consists of Phase Ia and Phase Ib, where Phase Ia is a dose-escalation stage.The Phase Ia will include histopathologically confirmed non-muscle-invasive bladder cancer (NMIBC) patients with high-risk stratification (including extremely high-risk).The Phase Ib study will include two independent cohorts: Cohort A comprises high-risk non-muscle-invasive bladder cancer (NMIBC) patients (carcinoma in situ \[CIS\], with or without Ta/T1 stage lesions) who have shown no response to BCG. Cohort B will include T2-4aN0-1M0 stage bladder cancer patients (clinically localized muscle-invasive bladder urothelial carcinoma).
• 1.The Phase Ia will include histopathologically confirmed non-muscle-invasive bladder cancer (NMIBC) patients with high-risk stratification (including extremely high-risk). High-risk stratification criteria are defined as G3/high-grade tumors that meet any of the following criteria: carcinoma in situ (CIS); stage T1; diameter\>3 cm; multiple tumors; or recurrent tumors. The Phase Ib Cohort A will include BCG unresponsive NMIBC patients with carcinoma in situ \[CIS\], with or without Ta/T1 stage lesions, while Cohort B will include histopathologically confirmed muscle-invasive bladder cancer (cT2-4aN0-1M0).Note: BCG non-response is defined as meeting any of the following criteria: 1. Persistent or recurrent CIS within 12 months after completing adequate BCG treatment; 2. Recurrence of high-grade Ta/Tl disease within 6 months after completing adequate BCG treatment; 3. High-grade T1 disease at first evaluation after induction BCG treatment. (Adequate BCG treatment is defined as: Complete at least 5 out of 6 doses in the initial induction course. plus 2 out of 6 doses from the second induction course, or 2 doses from the 3-dose maintenance course.)
• 2.Excluding Phase Ib Cohort B, participants must either be medically ineligible for radical cystectomy as determined by urologists or have declined the procedure.
• 3.Age 18 to 75 (including 18 and 75).
• 4.Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 to 1.
• 5.Estimated survival time is ≥2 years.6.No dysfunction of major organs, including but not limited to hematopoietic function and cardiac, pulmonary,hepatic and renal function.
• Hematologic system (no history of blood transfusion or hematopoietic growth factor treatment within 14 days)
⁃ Absolute neutrophil count (ANC)≥1.5×109/L
⁃ Platelets （PLT）≥75×109/L
⁃ Hemoglobin （Hb）≥90g/L
• Hepatic function
⁃ Total bilirubin (TBIL)≤1.5× upper limit (ULN)
⁃ Alanine aminotransferase (ALT)≤3×ULN
⁃ Aspartate aminotransferase (AST)≤3×ULN
• Renal function
⁃ Creatinine （Cr）≤1.5×ULN
⁃ Creatinine clearance (Ccr) (Calculation required only if creatinine exceeds 1.5×ULN)\>50 mL/min (calculated using the Cockcroft-Gault formula)
• Coagulation function
⁃ Activated Partial Thromboplastin Time (APTT)≤1.5×ULN
⁃ International normalized ratio (INR)≤1.5×ULN
∙ 7.Premenopausal patients must have a negative blood pregnancy test during the screening period;they must agree to use reliable contraceptive methods (barrier contraceptive method or abstinence) with their partners during the trial and for at least 6 months after the last dose.
‣ 8.Patients must provide informed consent to the trial and voluntarily sign of a written informed consent form before participating in the trial.