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

Prior treatment

• 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.
• 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.
• 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.
• 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.
• 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.
• Requirement for long-term high-dose corticosteroid therapy or other immunosuppressive therapy that, in the investigator's judgment, may interfere with study treatment.
• Major surgery, definitive radiotherapy, or extensive palliative radiotherapy within 4 weeks before enrollment, or unresolved surgery- or radiotherapy-related toxicity above Grade 1.
• Another malignancy within the previous 5 years, except for malignancies that have been definitively treated and are considered to have a low risk of recurrence, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical carcinoma in situ, low-risk prostate cancer, or adequately treated non-muscle-invasive bladder cancer.

Other illness

• Known hypersensitivity to disitamab vedotin, toripalimab, cetirizine, mecobalamin, or any component of these agents.
• 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.
• 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 \<500 IU/mL may be enrolled. HBV DNA testing is required only for participants who are positive for hepatitis B core antibody.
• Active hepatitis C infection. Participants with a negative hepatitis C virus (HCV) antibody test during screening, or those with a positive HCV antibody test but negative HCV RNA, may be enrolled. Participants with a positive HCV antibody test must undergo HCV RNA testing.
• History of immunodeficiency, including positive human immunodeficiency virus (HIV) testing or other acquired or congenital immunodeficiency disorders, or a history of allogeneic stem cell transplantation or organ transplantation.
• Drug or alcohol abuse, severe psychiatric illness, cognitive impairment, or any other condition that may interfere with the ability to provide informed consent, comply with study treatment, or complete follow-up.

Lab values

• 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.

Other

• Pregnant or breastfeeding women.

• 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.
• Age ≥18 years, regardless of sex.
• 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.
• HER2 expression ≥1+ by immunohistochemistry, as determined at the local laboratory using a pretreatment tumor specimen.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ function, as demonstrated by the following laboratory values obtained within 14 days before enrollment:
  • 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).
  • Total serum bilirubin ≤1.5 × ULN; for participants with Gilbert syndrome or predominantly indirect hyperbilirubinemia of extrahepatic origin, total bilirubin must be ≤3 × ULN.
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 × ULN.
• At least one measurable lesion according to RECIST version 1.1.
• 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.
• No peripheral neuropathy at enrollment. Participants with a history of peripheral neuropathy must have Grade 0 peripheral neuropathy at enrollment.
• 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.