DV Plus Toripalimab With Cetirizine and Mecobalamin Pretreatment in Patients With Locally Advanced Unresectable or Metastatic Bladder Cancer

This is a prospective, open-label, single-arm exploratory clinical study evaluating the efficacy and safety of disitamab vedotin (RC48) plus toripalimab with cetirizine and mecobalamin in patients with locally advanced unresectable or metastatic bladder cancer who have not received prior systemic therapy for advanced disease. Disitamab vedotin is a HER2-targeted antibody-drug conjugate, and toripalimab is a PD-1 immune checkpoint inhibitor. Although antibody-drug conjugates have shown antitumor activity in urothelial cancer, treatment-related peripheral neuropathy may affect patients' quality of life and the ability to continue treatment. In this study, cetirizine and mecobalamin are incorporated as a supportive and preventive strategy to explore whether they may help reduce or delay treatment-related peripheral neuropathy while maintaining antitumor activity. Approximately 10 to 20 participants will be enrolled. The primary outcomes are objective response rate according to RECIST v1.1 and the incidence of treatment-related Grade 2 or higher peripheral neuropathy. Secondary outcomes include overall safety, disease control rate, progression-free survival, and overall survival. Exploratory analyses will evaluate changes in the tumor immune microenvironment, including CD8-positive T-cell infiltration and activation, and their associations with treatment response and peripheral neuropathy.

Inclusion Criteria: 1. Voluntarily agrees to participate in the study, is able to provide written informed consent, and is able to understand and comply with the study requirements and assessment schedule. 2. Age ≥18 years, regardless of sex. 3. Histologically or cytologically confirmed bladder urothelial carcinoma, including pure urothelial carcinoma or mixed bladder carcinoma with a predominant urothelial carcinoma component (≥50%), with clinically diagnosed unresectable locally advanced, recurrent, or metastatic disease that is not suitable for curative surgery or definitive radiotherapy. 4. HER2 expression ≥1+ by immunohistochemistry, as determined at the local laboratory using a pretreatment tumor specimen. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Adequate organ function, as demonstrated by the following laboratory values obtained within 14 days before enrollment: a. The following hematologic criteria must be met without growth factor support within 14 days before sample collection: i. Absolute neutrophil count ≥1.5 × 10\^9/L; ii. Platelet count ≥90 × 10\^9/L; iii. Hemoglobin ≥90 g/L. b. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 × the upper limit of normal (ULN). c. Total serum bilirubin ≤1.5 × ULN; for participants with Gilbert syndrome or predominantly indirect hyperbilirubinemia of extrahepatic origin, total bilirubin must be ≤3 × ULN. d. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 × ULN. 7. At least one measurable lesion according to RECIST version 1.1. 8. Any adverse events related to prior anticancer treatment must have recovered to Grade 0 or 1 before enrollment, except for clinically insignificant toxicities such as alopecia, pigmentation changes, or stable endocrine abnormalities controlled with replacement therapy. 9. No peripheral neuropathy at enrollment. Participants with a history of peripheral neuropathy must have Grade 0 peripheral neuropathy at enrollment. 10. Female participants of childbearing potential must have a negative pregnancy test before enrollment and agree to use effective contraception during study treatment and for the protocol-specified period after the last dose. Male participants with partners of childbearing potential must also agree to use effective contraception. Exclusion Criteria: 1. Prior systemic anticancer treatment for advanced, recurrent, or metastatic bladder cancer, including chemotherapy, immunotherapy, targeted therapy, antibody-drug conjugates (ADCs), or other investigational anticancer agents. 2. Prior treatment with disitamab vedotin, another HER2-targeted ADC, or an MMAE-containing ADC; or a history of severe immune-related adverse events associated with prior treatment with PD-1, PD-L1, CTLA-4, or other immune checkpoint inhibitors. 3. Known hypersensitivity to disitamab vedotin, toripalimab, cetirizine, mecobalamin, or any component of these agents. 4. Grade 2 or higher peripheral neuropathy, or a severe neurologic disorder that, in the investigator's judgment, may interfere with assessment of neurotoxicity, including but not limited to severe diabetic peripheral neuropathy, spinal cord compression, severe spinal canal stenosis, active neuritis, or demyelinating disease. 5. Active or previously diagnosed autoimmune disease that may worsen with PD-1 inhibitor therapy, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, systemic sclerosis, vasculitis, autoimmune hepatitis, or multiple sclerosis. 6. Receipt of a live vaccine within 28 days before enrollment. Seasonal injectable influenza vaccines that are inactivated are permitted; intranasal live vaccines are not permitted. 7. Active central nervous system metastases, leptomeningeal metastases, or carcinomatous meningitis. Participants with previously treated brain metastases may be considered eligible if the lesions are stable, the participant is asymptomatic, corticosteroids have been discontinued or reduced to a low dose, and enrollment is considered safe by the investigator. 8. Requirement for long-term high-dose corticosteroid therapy or other immunosuppressive therapy that, in the investigator's judgment, may interfere with study treatment. 9. Clinically significant abnormalities of potassium, sodium, or calcium; hypoalbuminemia; interstitial lung disease; noninfectious pneumonitis; or other uncontrolled systemic diseases that, in the investigator's judgment, may interfere with study treatment, including uncontrolled diabetes mellitus, hypertension, or cardiovascular disease. This includes active cardiac disease within 6 months before enrollment, such as severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, or ventricular arrhythmias requiring medical treatment. 10. Untreated chronic hepatitis B infection or hepatitis B virus (HBV) carrier status with HBV DNA ≥500 IU/mL (2500 copies/mL). Participants who are inactive hepatitis B surface antigen carriers or who have stable active HBV infection after continuous antiviral therapy with HBV DNA \