A Study to Evaluate the Efficacy and Safety of Intravesical Instillation of Disitamab Vedotin Combined With Toripalimab in Patients With HER2-Positive High-Risk Non-Muscle Invasive Bladder Cancer Who Are BCG-Naïve or Have BCG Failure

An Open-Label, Single-Arm Clinical Study to Evaluate the Efficacy and Safety of Intravesical Instillation of Disitamab Vedotin Combined With Toripalimab in Patients With HER2-Positive High-Risk Non-Muscle Invasive Bladder Cancer Who Are BCG-Naïve or Have BCG Failure

This study is an open-label, single-arm investigator-initiated clinical trial, aiming to evaluate the efficacy and safety of vicedetinib bladder instillation combined with teprotumumab in the treatment of patients with HER2-expressing, previously untreated, or BCG-resistant high-risk non-muscle-invasive bladder cancer (NMIBC). The subjects to be included in the study must have undergone standard TURBT within 3 weeks before enrollment, removed all visible lesions, and had a clear pathological diagnosis of NMIBC, with their risk classification according to the "Chinese Bladder Cancer Diagnosis and Treatment Guidelines (2022)" falling into the high-risk group (including extremely high-risk group). All surgical tumor specimens of the included subjects underwent HER2 testing, indicating HER2 expression, defined as immunohistochemistry (IHC) 1+, 2+ or 3+, with FISH verification for amplification if IHC 2+ is present. The subjects were divided into two groups based on whether they had received BCG treatment in the past: one group was high-risk NMIBC patients who had not received BCG treatment, including one of the following situations: ① refused BCG treatment, ② had contraindications to BCG use, ③ BCG was inaccessible; the other group was high-risk NMIBC patients who had no response to BCG, meeting any of the following criteria: ① had persistent/recurrent high-risk NMIBC within 12 months (±1 month) after adequate BCG treatment, ② had high-grade T1 disease during the first assessment after induction BCG treatment. Adequate BCG treatment was defined as completing at least 5 BCG bladder instillations within 2 months, and then at least 2 BCG bladder instillations for 6 consecutive weeks within the next 10 months, meaning at least "5+2" BCG bladder instillations within approximately 12 months. Eligible subjects received vicedetinib bladder instillation combined with teprotumumab treatment; vicedetinib was administered once weekly at 180mg for 8 times. For patients receiving treatment, if there was no occurrence of persistent/recurrent NMIBC, disease progression, or intolerable toxicity, they would receive maintenance bladder instillation with vicedetinib for one year, with the maintenance regimen being: once every 4 weeks for 10 times. Teprotumumab: 240mg per dose, intravenous, once every 3 weeks for 1 year. Patients were required to collect urine samples before the first treatment and after the last treatment. Safety during the study was evaluated according to the NCI-CTCAE V5.0 standard, and the observation indicators included vital signs, physical examination, laboratory tests, electrocardiogram and echocardiogram examinations, adverse events and serious adverse events.

Study Overview

• Status: Not yet recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Intravesical Instillation of Disitamab Vedotin Combined with Toripalimab

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Huihuang Li, Doctor of Medicine; Phone Number: +86-731-8975-3011; Email: lhhuang1994@163.com

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China
      • Xiangya Hospital
      • Contact: Huihuang Li, Doctor of Medicine; Phone Number: +86-731-8975-3011; Email: lhhuang1994@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily agree to participate in the research and sign the informed consent form.
2. Within 3 weeks after TURBT surgery, the tumor tissue specimens obtained from the subjects were subjected to immunohistochemical (IHC) testing for HER2 expression, which met the criteria of 1+, 2+ or 3+. If the IHC result was 2+, FISH verification for amplification was required.
3. ECOG physical condition: 0 - 2 points.
4. Sufficient heart, bone marrow, liver and kidney functions should meet the following standards within 7 days before the drug administration study (normal values are based on the clinical trial center): Left ventricular ejection fraction ≥ 50%; Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelets ≥ 100 × 10^9/L; Serum total bilirubin ≤ 1.5 times the upper limit of normal value (ULN); ALT and AST ≤ 2.5 × ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance rate (CrCl) ≥ 50 mL/min according to the Cockcroft-Gault formula.
5. Within 3 weeks after TURBT surgery, the tumor tissue specimens obtained from the subjects were subjected to immunohistochemical (IHC) testing for HER2 expression, which met the criteria of 1+, 2+ or 3+. If the IHC result was 2+, FISH verification for amplification was required.
6. ECOG physical condition: 0 - 2 points.
7. Sufficient heart, bone marrow, liver and kidney functions should meet the following standards within 7 days before the drug administration study (normal values are based on the clinical trial center): Left ventricular ejection fraction ≥ 50%; Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelets ≥ 100 × 10^9/L; Serum total bilirubin ≤ 1.5 times the upper limit of normal value (ULN); ALT and AST ≤ 2.5 × ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance rate (CrCl) ≥ 50 mL/min according to the Cockcroft-Gault formula.
8. The female subjects should be patients who have undergone surgical sterilization or menopause, or those who agree to use at least one medically approved contraceptive method (such as intrauterine device, contraceptive pills or condoms) during the study treatment period and within 6 months after the end of the study treatment. The blood pregnancy test must be negative within 7 days before the subject is enrolled in the study. False positive results can be excluded after confirming pregnancy by the investigator and then the subject can be enrolled. Male subjects should agree to use at least one medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment.
9. Willing and able to comply with the arrangements of the trial and follow-up procedures.
10. Willing and able to comply with the arrangements of the trial and follow-up procedures.

Exclusion Criteria:

1. Muscle-invasive bladder cancer (T2 and above) and/or those with regional lymph node and distant metastasis.
2. Combined urinary tract urothelial carcinoma outside the bladder (i.e., in the urethra, ureters or renal pelvis).
3. The study excluded any patients who had received any other anti-tumor treatments within 4 weeks prior to the administration of the drug, such as chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc. This exclusion did not include the one-time perfusion chemotherapy immediately performed after TURBT.
4. Before the start of the drug study, there was no recovery from the adverse events caused by the previously used anti-tumor drugs to the 0-1 level of CECAT within 2 weeks.
5. Those who started the drug administration within 4 weeks before the study or those who planned to undergo major surgery during the trial period.
6. Serological virological examination (based on the normal values of the research center): HBsAg or HBcAb test results are positive, and HBVDNA copy number is also positive; HCVAb test result is positive, and HCV RNA test result is also positive; HIVAb test result is positive.
7. The study excluded participants who had received live vaccines within 4 weeks prior to the start of the treatment or who planned to receive any vaccines during the study period (except for the novel coronavirus inactivated virus vaccine).
8. Heart failure classified as grade 3 or above by the New York Heart Association (NYHA) in the United States.
9. The study excluded cases where there had been severe arterial/venous thrombosis events or cardiovascular/cerebrovascular accidents within 6 months before administration, such as deep vein thrombosis, pulmonary embolism, cerebral infarction, cerebral hemorrhage, myocardial infarction, etc. However, cases of asymptomatic and non-requirement-of-clinical-intervention lacunar cerebral infarction were included.
10. There are active or progressive infections that require systematic treatment, such as active tuberculosis.
11. There are systemic diseases that have been judged by the researchers to be active and not yet under stable control, as well as severe comorbidities, including diabetes, hypertension, liver cirrhosis, interstitial pneumonia, obstructive pulmonary disease, etc.
12. Previous history of receiving allogeneic hematopoietic stem cell transplantation or organ transplantation.
13. Those who are known to be allergic to RC48-ADC/Teripipor or any of its components or any of the excipients.
14. Pregnant or lactating women.
15. It is estimated that the patient's compliance with this clinical study is insufficient.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intravesical Instillation of Disitamab Vedotin Combined with Toripalimab; Eligible subjects will be enrolled and treated with intravesical instillation of disitamab vedotin combined with toripalimab. Disitamab vedotin will be administered at a dose of 180 mg once weekly for 8 consecutive cycles. For treated patients without persistent/recurrent NMIBC, disease progression, or intolerable toxicity, maintenance intravesical instillation of disitamab vedotin will be performed within 1 year. The regimen for maintenance therapy is 180 mg once every 4 weeks for 10 consecutive cycles. Toripalimab will be administered intravenously at a dose of 240 mg once every 3 weeks for 1 consecutive year.

Drug: Intravesical Instillation of Disitamab Vedotin Combined with Toripalimab; Eligible subjects will be enrolled and treated with intravesical instillation of disitamab vedotin combined with toripalimab. Disitamab vedotin will be administered at a dose of 180 mg once weekly for 8 consecutive cycles. For treated patients without persistent/recurrent NMIBC, disease progression, or intolerable toxicity, maintenance intravesical instillation of disitamab vedotin will be performed within 1 year. The regimen for maintenance therapy is 180 mg once every 4 weeks for 10 consecutive cycles. Toripalimab will be administered intravenously at a dose of 240 mg once every 3 weeks for 1 consecutive year.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The one-year recurrence-free survival rate of patients with high-risk NMIBC	After all subjects have been enrolled and followed up for an additional 12 months, or upon achievement of the required number of positive events, Recurrence-Free Survival (RFS) will be analyzed using the Kaplan-Meier method. The median recurrence-free time will be estimated via the Kaplan-Meier method. Hazard ratios (HR) and their 95% confidence intervals will be calculated using the Cox proportional hazards model.	One year after the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The clinical complete remission rates for 3 months and 6 months	the proportion of patients achieving clinical complete remission at 3 months and 6 months.	Three months and six months after the treatment
Overall survival period	Overall Survival (OS) is defined as the time from the date of initial treatment to death from any cause. Patients who remain alive at the last follow-up will be censored.	through study completion, an average of 3 years
Progression-free survival time	Progression-free survival (PFS) is defined as the time from the initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first.	through study completion, an average of 3 years
Adverse event	An adverse event (AE) is any unfavorable or unintended medical occurrence in a subject administered a study drug, which does not necessarily have a causal relationship with the study treatment.	through study completion, an average of 3 years

Collaborators and Investigators

• Sponsor: Xiangya Hospital of Central South University

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): February 1, 2030

Study Registration Dates

• First Submitted: April 20, 2026
• First Submitted That Met QC Criteria: August 23, 2026
• First Posted (Actual): August 25, 2026

Study Record Updates

• Last Update Posted (Actual): August 25, 2026
• Last Update Submitted That Met QC Criteria: August 23, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: HER2; Toripalimab; Bladder instillation; Disitamab Vedotin; High-risk non-muscle-invasive bladder cancer
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; toripalimab
• Other Study ID Numbers: Xiangya202604051

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No