This is a prospective, multicenter, Phase Ib clinical study designed to evaluate the safety and preliminary efficacy of propranolol combined with tislelizumab plus gemcitabine/cisplatin (GC) as neoadjuvant therapy for patients with bladder urothelial carcinoma with clinical lymph node involvement (cT1-T4aN1-3M0). Current neoadjuvant immunochemotherapy regimens can improve clinical outcomes in cisplatin-eligible patients; however, patients with lymph node metastasis show a significantly poorer pathological complete response (pCR) rate compared with non-metastatic cases. Real-world clinical observations have shown that more than 20% of patients achieve complete response in the primary tumor after immunotherapy but have persistent or progressive positive lymph nodes, suggesting unique resistance mechanisms within lymph node metastatic lesions. Preclinical studies conducted by our team demonstrated that sympathetic innervation within lymph nodes releases norepinephrine, which activates β-adrenergic signaling in metastatic tumor cells and promotes lipid metabolic reprogramming, leading to CD8⁺ T-cell exhaustion and immune resistance. Propranolol, a non-selective β-adrenergic blocker, may reduce metabolic stress and restore antitumor immunity, potentially enhancing the efficacy of immune checkpoint blockade. In this study, enrolled patients will receive oral propranolol in combination with intravenous tislelizumab and standard GC chemotherapy prior to surgery. Participants will be closely monitored for treatment-related adverse events, including cardiovascular events, hematologic toxicity, and immune-related reactions. The primary endpoint is dose-limiting toxicity (DLT). Secondary endpoints include pathological complete response (pCR), pathological downstaging, safety, and survival outcomes. Exploratory analyses will evaluate changes in immune cell populations in tumor tissues, lymph nodes, and peripheral blood. The results of this study aim to provide evidence for new neoadjuvant strategies targeting lymph node metastatic bladder cancer and support the development of personalized therapeutic approaches.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Propranolol will be administered orally as a non-selective β-adrenergic receptor blocker. Treatment will start at a low dose and may be escalated to a maximum of 40 mg twice daily if tolerated. Vital signs will be monitored regularly, and dose adjustment, interruption, or discontinuation may occur based on predefined cardiovascular safety criteria.
Tislelizumab will be administered intravenously as an anti-PD-1 monoclonal antibody according to standard dosing schedules for neoadjuvant immunotherapy. Infusion monitoring will be conducted in a facility equipped for emergency management. Dose interruption or discontinuation may occur if immune-related adverse events develop.
Gemcitabine will be administered intravenously as part of the gemcitabine/cisplatin chemotherapy regimen during neoadjuvant treatment. Hematologic parameters and organ function will be regularly monitored, and chemotherapy dose may be modified based on toxicity and tolerability according to institutional standards.
Cisplatin will be administered intravenously as part of the gemcitabine/cisplatin regimen. Renal function, electrolyte balance, and hematologic tests will be routinely monitored. Dosing may be adjusted or withheld according to predefined safety criteria and institutional guidelines for cisplatin-based chemotherapy.
Incidence of Dose-Limiting Toxicities (DLTs)
Dose-limiting toxicities (DLTs) are defined as treatment-related adverse events occurring during the first treatment cycle that meet predefined severity criteria based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. DLTs may include grade 3 or higher non-hematologic toxicity, grade 4 hematologic toxicity, or clinically significant events leading to treatment interruption or discontinuation, as determined by the investigators.
Time frame: At the end of Cycle 1 (each cycle is 28 days)
Pathological Complete Response (pCR) Rate
Pathological complete response (pCR) is defined as the absence of any residual tumor in the primary bladder lesion and in all examined regional lymph nodes following neoadjuvant therapy and surgical resection (pT0N0). The proportion of participants achieving pCR will be calculated relative to the total number of evaluable participants.
Time frame: At the time of surgery
Pathological Downstaging Rate
Pathological downstaging is defined as a postoperative pathological tumor stage (ypT) lower than the baseline clinical stage (cT), with downstaging to ypT2 or lower considered as treatment-induced downstaging. The proportion of evaluable participants achieving pathological downstaging will be recorded.
Time frame: At the time of surgery
Incidence of Treatment-Related Adverse Events
Adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) will be collected and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Events will be summarized by frequency, severity grade, and relationship to study treatment.
Time frame: From first dose through 30 days after the last administration of study treatment
Progression-Free Survival (PFS)
PFS is defined as the time from study enrollment to the first documented disease progression, local or distant recurrence, or death from any cause, whichever occurs first. Participants without an event will be censored at the date of last disease assessment.
Time frame: Up to 24 months after surgery
Overall Survival (OS)
OS is defined as the time from study enrollment to death from any cause. Participants who remain alive at the end of follow-up will be censored at the date of last known contact.
Time frame: Up to 36 months after surgery
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