When bladder cancer patients are treated to mobilize their own immune system to fight the tumor, drugs that kill the bacteria can impair the effectiveness of the treatment. The purpose of this study is to find out if the common dietary supplement Vitamin B3 could allow drugs that kill bacteria to not negatively affect treatments that mobilize the immune system to fight tumors.
The patient voluntarily agrees to participate, is able to provide written informed consent, and is willing and able to comply with the protocol and schedule of assessments.
Aged ≥18 years on the date of signing the informed-consent form (ICF).
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 1).
Residual tumour after TURBT and histologically confirmed urothelial carcinoma of the bladder staged cT2-T4a N0 M0 by AJCC 8th edition imaging; for mixed-histology tumours, the urothelial component must be predominant (≥50 %).
Previous therapy directed against PD-1, PD-L1, PD-L2, CTLA-4 or any other antibody or drug targeting T-cell co-stimulation or checkpoint pathways.
Systemic anticancer therapy or systemic immunomodulator (e.g. interferon, interleukin-2, TNF) within 28 days before enrolment.
Prior radiotherapy to the bladder.
≥12 months since the last dose of systemic chemotherapy before study neoadjuvant therapy;
Single group
Tislelizumab, Cisplatin, Gemcitabine and Vitamin B3
Drug1. Tislelizumab: 200mg, 1x time at d1 each cycle 2. Gemcitabine: 1000mg/ m2, in d1, d8 each cycle 3. Cisplatin: 70 mg/m2, in d2 each cycle Tislelizumab maintenance therapy: after chemoimmunotherapy, 200mg, q3W. 4. Vitamin B3 tablet(also known as nicotinic acid tablet) supplementation daily(300mg QD or 500mg QD) after antibiotic treatment.
Phase I: The DLT dose of the Vitamin B3
Participants with dose-limiting toxicity (DLT) asassessed by NCl CTC 5.0 and the administered drug dose.
Percentage of Participants With Pathological Downstaging(pDS)
The pathological downstaging rate is defined as the evaluation of whether the staging is degraded to ≤ T2 based on the post-surgery pathological findings. The rates of cT2N0 → pT0N0, cT3-4aN0 → pT0N0, cT2N0 → ≤ pT1N0, cT3-4aN0 → ≤ pT1N0 will be calculated, and the 2 sided Clopper-Pearson 95% confidence interval (CI) of pathological downstaging rate will be calculated to assess the precision of the estimated pathological downstaging rate.
Safety and AE
Number of unique patients who had a treatment-related (possible, probable, or definite) adverse event using the Medical Dictionary for Regulatory Activities (MedDRA) terms and graded per NCI-CTCAE v5.0. Number and Grade of patients who had a surgery-related adverse event (surgery-related AE) will be measured according to the Clavien-Dindo classification.
Percentage of Participants With Pathological Complete Response(pCR)
Pathological evaluation of the resected tumor tissue and regional lymph nodes showed no residual tumor cells, complete disappearance of the tumor lesions, and no evidence of new lesions.
Biomarker Endpoint Analyses
To explore biomarkers in urine, blood, and tumor tissues (collected from TURBT) atbaseline and tissue samples collected from radical cystectomy. Biomarkers include PD-L1, Mki67 expression in tumor tissues, immune cells profling and gene expression and tumor mutation profiling.
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