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.
1.Evidence of metastatic disease, or multiple regional lymph node positivity in the true pelvis, or common iliac lymph node positivity at the screening visit. Accompanied by hydronephrosis.
2.Received pelvic external beam radiation therapy within 5 years.
3.Prior treatment with adenovirus-based therapies (e.g., oncolytic adenovirus, CanSino's Ad5-nCoV COVID-19 vaccine).
4.Symptomatic urinary tract infection or bacterial cystitis (patients can enter the study once the treatment is satisfactory).
Single group
KD01(the recombinant oncolytic adenovirus)
DrugDrug： Phase Ia：KD01(3 dose groups: 2.6×10¹¹ VP, 5×10¹¹ VP, and 1×10¹² VP) Phase Ib: KD01(5×10¹¹ VP) with AK104(6 mg/kg, given intravenously every two weeks) Administration： Phase Ia: KD01 will be administered weekly during weeks 1-6, 13-15, 25-27, 37-39, 49-51, 73, 97. If patients present with CIS and/or high-grade Ta at the first efficacy assessment in week 12, KD01 will be administered weekly during weeks 16-18. Phase Ib Cohort A: KD01 for the same treatment duration as Phase Ia. AK104: The initial 6 doses will be administered, and subsequent doses will be continued based on the investigator's assessment of the patient's condition and the patient's willingness. Phase Ib Cohort B: KD01 will be administered weekly during weeks 1-6,with AK104 (3 doses). A transurethral resection of the bladder tumor (TURBT) is recommended 2-4 weeks after the final KD01 dose for residual or suspicious tumors, with subsequent treatment determined by investigators based on imaging results.
SAEs and AEs（Phase Ia）
The incidence of serious adverse events (SAEs), the incidence and severity of adverse events (AEs).
MTD
Phase Ia: The maximum tolerated dose (MTD) is determined based on the incidence of dose-limiting toxicity (DLT).
SAEs and AEs（Phase Ib）
The incidence of serious adverse events (SAEs), the incidence and severity of adverse events (AEs).
CRR(Phase Ia and Phase Ib Cohort A)
Phase Ia and Phase Ib Cohort A: Complete Response (CR) rates at any time points and at 3, 6, 12,15,18, and 24 months.
DOR（Phase Ia and Phase Ib Cohort A）
Phase Ia and Phase Ib Cohort A: Duration of Response (DOR) at these time points.
CRR(Phase Ib Cohort B)
Phase Ib Cohort B: includes the incidence of pathological complete response (pT0N0) .
PRR(Phase Ib Cohort B)
Phase Ib Cohort B: includes the incidence of pathological partial response（\<pT2N0）.
Antibodie
Dynamic changes in anti-Ad5 adenovirus antibodies.
Neutralizing antibodies
Dynamic changes in neutralizing antibodies.
Immunogenicity
The immunogenicity of KD01 via ELISPOT or ICS.
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