Neoadjuvant RC48 Plus Gemcitabine in HER2-Expressing MIBC

July 6, 2026 updated by: Zhiquan Hu

Neoadjuvant RC48 Plus Gemcitabine for HER2 1~3+ MIBC: A Prospective, Multicenter, Randomized, Controlled, Non-inferiority Study (GUARD-02)

Objectives: To evaluate the non-inferiority of disitamab vedotin plus gemcitabine versus disitamab vedotin plus toripalimab in terms of the pathological complete response (pCR) rate as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC).

This study is designed to evaluate two parallel neoadjuvant treatment strategies followed by definitive local therapy and adjuvant treatment. Eligible patients will be assigned to either the Experimental Arm, receiving neoadjuvant Disitamab Vedotin (RC48) combined with Gemcitabine, or the Active Comparator Arm, receiving neoadjuvant RC48 combined with Toripalimab. Both neoadjuvant regimens are administered every two weeks for 3 to 6 cycles, contingent upon imaging-based tumor response. Following the neoadjuvant phase, patients from both arms will proceed to receive standard Radical Cystectomy (RC) combined with Pelvic Lymph Node Dissection (PLND) within four weeks of their final dose, with a trimodality therapy (TMT) bladder-sparing approach strictly restricted to a selected minority of patients. In the postoperative phase, eligible patients will receive adjuvant therapy consisting of RC48 plus Toripalimab for 6 cycles, followed by Toripalimab maintenance monotherapy for a duration of ≤ 1 year (or a maximum of 1 year).Patients post-RC require abdominopelvic/chest imaging q3-6m; non-RC patients need cystoscopy q3m and abdominopelvic/chest CT q3-6m. Follow-up staff should proactively contact patients q3m to record imaging findings and inquire about hematuria, stomal lesions, cough/chest pain, CNS symptoms, and accurately document recurrence/progression, metastasis, death with dates.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

170

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Anhui
      • Hefei, Anhui, China, 230022
        • Recruiting
        • The First Affiliated Hospital of Anhui Medical University
        • Contact:
          • Hanjiang Xu, M.D.
          • Phone Number: 18326170623
        • Principal Investigator:
          • Hanjiang Xu, M.D.
    • Fujian
      • Fuzhou, Fujian, China, 350001
        • Recruiting
        • Fujian Medical University Union Hospital
        • Contact:
        • Principal Investigator:
          • Shaoxing Zhu, M.D.
      • Xiamen, Fujian, China, 361003
        • Recruiting
        • The First Affiliated Hospital of Xiamen University
        • Principal Investigator:
          • Wei Li, M.D.
        • Contact:
          • Wei Li, M.D.
          • Phone Number: 13666028912
    • Guangdong
      • Guangzhou, Guangdong, China, 510280
        • Recruiting
        • ZhuJiang Hospital of Southern Medical University
        • Contact:
        • Principal Investigator:
          • Abai Xu, M.D.
      • Shenzhen, Guangdong, China, 518117
        • Recruiting
        • Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center
        • Contact:
        • Principal Investigator:
          • Dongwen Wang, M.D.
    • Hubei
      • Enshi, Hubei, China, 445000
        • Recruiting
        • The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture
        • Contact:
          • Su Chen, M.D.
          • Phone Number: 13477894099
        • Principal Investigator:
          • Su Chen, M.D.
      • Huanggang, Hubei, China, 438000
        • Recruiting
        • Huanggang Central Hospital
        • Contact:
        • Principal Investigator:
          • Jiayi Tao, M.D.
      • Huangshi, Hubei, China, 435000
        • Recruiting
        • Huangshi Central Hospital
        • Contact:
        • Principal Investigator:
          • Dingwen Gui, M.D.
      • Jingmen, Hubei, China, 448000
        • Recruiting
        • Jingmen Central Hospital
        • Contact:
        • Principal Investigator:
          • Zeming Liao, M.D.
      • Jingzhou, Hubei, China, 434020
        • Recruiting
        • Jingzhou Central Hospital
        • Contact:
        • Principal Investigator:
          • Yixiang Liao, M.D.
      • Jingzhou, Hubei, China, 434000
        • Recruiting
        • Jingzhou First People's Hospital
        • Contact:
        • Principal Investigator:
          • Haitao Dai, M.D.
      • Shiyan, Hubei, China, 442000
        • Recruiting
        • Taihe Hospital
        • Contact:
          • Congbo Chen, M.D.
          • Phone Number: 13907204825
        • Principal Investigator:
          • Congbo Chen, M.D.
      • Wuhan, Hubei, China, 430071
        • Recruiting
        • Zhongnan Hospital of Wuhan University
        • Contact:
        • Principal Investigator:
          • Xingyuan Xiao, M.D.
      • Wuhan, Hubei, China, 430060
        • Recruiting
        • Renmin Hospital of Wuhan University
        • Contact:
        • Principal Investigator:
          • Zhiyuan Chen, M.D.
      • Wuhan, Hubei, China, 430079
        • Recruiting
        • Hubei Cancer Hospital
        • Contact:
        • Principal Investigator:
          • Diansheng Cui, M.D.
      • Wuhan, Hubei, China, 430022
        • Recruiting
        • Wuhan No.1 Hospital
        • Contact:
        • Principal Investigator:
          • Gaofeng Zhou, M.D.
      • Wuhan, Hubei, China, 430014
        • Recruiting
        • The Central Hospital of Wuhan
        • Contact:
        • Principal Investigator:
          • Yonglian Guo, M.D.
      • Wuhan, Hubei, China, 430030
        • Recruiting
        • Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
        • Contact:
        • Principal Investigator:
          • Zhiquan Hu, M.D.
        • Sub-Investigator:
          • Chunguang Yang, M.D.
        • Sub-Investigator:
          • Haijun Huang, M.M.
      • Xiangyang, Hubei, China, 441021
        • Recruiting
        • Xiangyang Central Hospital
        • Contact:
        • Principal Investigator:
          • Bin Chen, M.D.
      • Yichang, Hubei, China, 443003
        • Recruiting
        • Yichang Central People's Hospital
        • Contact:
        • Principal Investigator:
          • Xiaobo Chen, M.D.
    • Jiangxi
      • Nanchang, Jiangxi, China, 330006
        • Recruiting
        • Jiangxi Provincial People's Hospital
        • Contact:
          • Kehua Jiang, M.D.
          • Phone Number: 18571225053
        • Principal Investigator:
          • Kehua Jiang, M.D.
    • Shandong
      • Jinan, Shandong, China, 250117
        • Recruiting
        • Shandong Cancer Hospital And Institute
        • Principal Investigator:
          • Jiasheng Bian, M.D.
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Informed Consent & Compliance: Provision of signed informed consent and ability to comply with study procedures and follow-up requirements.
  2. Age: Age 18 to 75 years (inclusive).
  3. Planned Surgery: Planned to undergo radical cystectomy (RC) with lymph node dissection (LND).
  4. Clinical Stage: Clinical stage T2-T4aNxM0, as assessed by CT, MRI, or PET-CT.
  5. Pathology & Biomarker: Histologically confirmed predominant urothelial carcinoma by cystoscopic biopsy or transurethral resection of bladder tumor (TURBT), with HER2 expression of 1+ to 3+ determined by immunohistochemistry (IHC).
  6. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
  7. Adequate Organ Function: Laboratory values meeting the following criteria: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelet count ≥ 100 × 10^9/L; Hemoglobin ≥ 80 g/L; Total bilirubin ≤ 1.5 × upper limit of normal (ULN); Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × ULN
  8. Cardiac Function: New York Heart Association (NYHA) class < 3.
  9. Reproductive Status & Contraception: *Female: Must be surgically sterile, postmenopausal, or agree to use highly effective contraception during the study and for 6 months after the last dose of study treatment. Must not be lactating. *Male: Must agree to use a medically acceptable method of contraception (e.g., condoms, abstinence) during the study and for 6 months after the last dose of study treatment.

Exclusion Criteria：

  1. Receipt of live attenuated vaccine within 4 weeks prior to enrollment or planned receipt during the study period.
  2. Receipt of systemic chemotherapy, or anti-PD-1, anti-PD-L1, or HER2-targeted therapy within the past 6 months.
  3. Known hypersensitivity to gemcitabine, disitamab vedotin, toripalimab, or any of their excipients.
  4. Active, known, or suspected autoimmune disease.
  5. Known history of primary immunodeficiency.
  6. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
  7. Untreated acute or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. (Patients receiving continuous antiviral therapy with monitored viral loads may be eligible at the investigator's discretion).
  8. Uncontrolled concurrent illness including, but not limited to: human immunodeficiency virus (HIV) infection, active or poorly controlled severe infection, or evidence of uncontrolled systemic disease (e.g., severe psychiatric/neurological disorders, decompensated respiratory failure).
  9. History of other malignancies within the past 5 years, excluding clinically cured early-stage tumors.
  10. Active tuberculosis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental Arm (RC48 + Gemcitabine)
Patients in this arm receive neoadjuvant Disitamab Vedotin (RC48) at a dose of 2.0 mg/kg via intravenous (IV) infusion (60-90 minutes) on Day 1, followed by Gemcitabine 1000 mg/m² IV on Day 2. The regimen is administered every 2 weeks (Q2W). Tumor response is evaluated via imaging after 3 cycles. Patients who do not achieve a clinical complete response (cCR) will continue the treatment for an additional 3 cycles (totaling 3 to 6 cycles).
Drug: Gemcitabine
On Day 2 of each neoadjuvant therapy cycle, a dose of 1000 mg/m² is administered via intravenous infusion. The regimen is administered every 2 weeks (Q2W).
Drug: Disitamab Vedotin (RC48)
On Day 1 of each neoadjuvant therapy cycle, a dose of 2 mg/kg is administered via intravenous infusion over 30-60 minutes.
Procedure: Radical Cystectomy
Patients are scheduled to undergo radical cystectomy (RC) within 4 weeks after the last dose of neoadjuvant therapy, and the postoperative specimens will be assessed for pathological response.
Active Comparator: Active Comparator Arm (RC48 + Toripalimab)
Patients in this arm receive neoadjuvant Disitamab Vedotin (RC48) at a dose of 2.0 mg/kg via IV infusion (60-90 minutes) on Day 1, followed by Toripalimab 3 mg/kg IV on Day 2. The regimen is administered every 2 weeks (Q2W). Tumor response is evaluated via imaging after 3 cycles, with treatment continuing for a total of 3 to 6 cycles based on the tumor response evaluation.
Drug: Disitamab Vedotin (RC48)
On Day 1 of each neoadjuvant therapy cycle, a dose of 2 mg/kg is administered via intravenous infusion over 30-60 minutes.
Procedure: Radical Cystectomy
Patients are scheduled to undergo radical cystectomy (RC) within 4 weeks after the last dose of neoadjuvant therapy, and the postoperative specimens will be assessed for pathological response.
Drug: Toripalimab
On Day 2 of each neoadjuvant therapy cycle, a dose of 3 mg/kg is administered via intravenous infusion. The regimen is administered every 2 weeks (Q2W).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological Complete Response (pCR)
Time Frame: Within 1 week after completion of radical cystectomy.
Defined as the absence of residual viable tumor cells (ypT0N0) in RC+PLND specimens. Assessed post-surgery. Method: A central pathology review committee performs centralized, blinded independent review of slides from all eligible patients. Sites ship de-identified slides and clinical forms to a central lab for uniform anonymization, QC, H&E staining, and supplementary IHC if needed. All materials are fully de-identified, presented in random order without clinical data. Two senior uropathologists (associate professor level or above) read independently; consensus is final, otherwise a third senior pathologist adjudicates blindly. ypT and ypN are recorded.
Within 1 week after completion of radical cystectomy.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs) During Neoadjuvant Therapy
Time Frame: The period starting from the first administration of neoadjuvant therapy and extending through 4 weeks following the last dose.
Defined as the proportion of patients in the safety set experiencing at least one Grade ≥3 TRAE (CTCAE v5.0) during neoadjuvant therapy. Assessed from the first cycle to 4 weeks after the last cycle, with comprehensive tests each cycle, a scheduled visit 1 week after the last dose of each cycle, and immediate evaluation upon any alert or complaint. Method: Uniform site training, structured eCRF recording of AE terms, dates, grades, relatedness, actions, outcomes. An independent Clinical Endpoint Committee (CEC) conducts centralized, blinded review of all Grade ≥3 events for final adjudication.
The period starting from the first administration of neoadjuvant therapy and extending through 4 weeks following the last dose.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Complete Response (cCR)
Time Frame: Within 1 week after completion of radical cystectomy.
Defined as no clinical evidence of residual tumor in primary and regional nodes after neoadjuvant therapy, assessed hierarchically: surgical patients based on pathological pCR (ypT0/Tis ypN0); non-surgical patients based on imaging CR per RECIST 1.1 (target lesions disappear, nodes <10 mm, no new lesions). Assessed post-neoadjuvant. Method: Surgical patients use central pathology review (same as pCR); non-surgical patients use independent imaging review committee blinded to RECIST 1.1. A CEC reviews all data in blinded fashion, adjudicates cCR per hierarchy, ensuring uniformity.
Within 1 week after completion of radical cystectomy.
Event-Free Survival (EFS)
Time Frame: From date of first neoadjuvant dose until the date of first documented events above, whichever came first, assessed up to 36 months.
Defined as time from neoadjuvant start to first occurrence of: ① disease progression (local/regional recurrence, distant metastasis, or definite clinical progression); ② death from any cause; ③ initiation of new anti-cancer therapy due to progression or toxicity. Censored at last known event-free assessment. Assessed at scheduled visits. Method: A central follow-up unit conducts structured symptom queries; any suspected event triggers medical evaluation. All potential event materials (imaging, records, symptom logs, death certificates) are submitted to an independent CEC for blinded adjudication of event and date, final for analysis.
From date of first neoadjuvant dose until the date of first documented events above, whichever came first, assessed up to 36 months.
Overall Survival (OS)
Time Frame: From date of first neoadjuvant dose until the date of death from any cause, assessed up to 36 months.
Defined as time from neoadjuvant start to death from any cause. Assessed at scheduled visits. Method: Central follow-up unit collects objective death documents from multiple sources. The independent CEC reviews all documents in a fully blinded manner, verifies and adjudicates the exact date of death, which serves as the final basis for OS calculation.
From date of first neoadjuvant dose until the date of death from any cause, assessed up to 36 months.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Zhiquan Hu

Collaborators

Tongji Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 1, 2026

Primary Completion (Estimated)

July 1, 2028

Study Completion (Estimated)

July 1, 2029

Study Registration Dates

First Submitted

June 28, 2026

First Submitted That Met QC Criteria

July 6, 2026

First Posted (Actual)

July 9, 2026

Study Record Updates

Last Update Posted (Actual)

July 9, 2026

Last Update Submitted That Met QC Criteria

July 6, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TJ-IRB202605029

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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