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.
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.
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.
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.
Single group
Disitamab Vedotin
DrugDisitamab vedotin will be administered intravenously at 2.0 mg/kg every 2 weeks. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, initiation of a new anticancer therapy, or investigator decision to discontinue treatment.
Toripalimab
DrugToripalimab will be administered intravenously at 240 mg every 3 weeks. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, initiation of a new anticancer therapy, completion of protocol-specified treatment, or investigator decision to discontinue treatment.
Cetirizine
DrugCetirizine will be administered orally at 10 mg once daily during study treatment as a prophylactic/supportive intervention to explore its potential effects on treatment-related peripheral neuropathy and antitumor immune responses. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, initiation of a new anticancer therapy, or investigator decision to discontinue treatment.
Mecobalamin
DrugMecobalamin will be administered orally at 0.5 mg three times daily during study treatment as a prophylactic/supportive intervention to explore its potential effects on treatment-related peripheral neuropathy. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, initiation of a new anticancer therapy, or investigator decision to discontinue treatment.
Objective Response Rate (ORR)
The proportion of efficacy-evaluable participants whose best overall response is complete response (CR) or partial response (PR), as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR is calculated as the number of participants with CR or PR divided by the total number of efficacy-evaluable participants.
Incidence of Treatment-Related Grade 2 or Higher Peripheral Neuropathy
The proportion of participants in the safety analysis population who develop treatment-related Grade 2 or higher peripheral neuropathy during study treatment. Peripheral neuropathy will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 and may include peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, numbness, tingling, pain, burning sensation, hypoesthesia, muscle weakness, impaired fine motor function, or gait instability. Events will be considered treatment-related based on investigator assessment.
Incidence of Adverse Events and Serious Adverse Events
Safety will be assessed by the incidence and severity of adverse events (AEs), treatment-related adverse events (TRAEs), serious adverse events (SAEs), adverse drug reactions (ADRs), and immune-related adverse events (irAEs). Adverse events will be graded according to NCI-CTCAE version 5.0. Safety assessments will also include laboratory tests, vital signs, and other clinically relevant safety parameters.
Disease Control Rate (DCR)
The proportion of efficacy-evaluable participants whose best overall response is complete response (CR), partial response (PR), or stable disease (SD), as assessed according to RECIST version 1.1. DCR is calculated as (CR + PR + SD) divided by the total number of efficacy-evaluable participants.
Progression-Free Survival (PFS)
PFS is defined as the time from the first administration of study treatment to the first documented radiographic disease progression or death from any cause, whichever occurs first. Participants without progression or death at the time of analysis will be censored at the date of their last evaluable tumor assessment.
Overall Survival (OS)
OS is defined as the time from the first administration of study treatment to death from any cause. Participants who are alive at the time of analysis will be censored at the date they were last known to be alive.
Changes in Tumor, Neuroinflammatory, and Immune Biomarkers
Exploratory analyses will assess changes in biomarkers related to neural injury or neuroinflammation, HER2 expression, PD-L1 expression, and histamine-H1 receptor signaling. Associations between selected biomarkers and clinical outcomes, including ORR, PFS, OS, treatment response, and peripheral neuropathy, will also be explored.
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