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NCT Number: NCT07693959

Neoadjuvant RC48 Plus Gemcitabine in HER2-Expressing MIBC

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.

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Key information

Conditions

MIBC

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Informed Consent & Compliance: Provision of signed informed consent and ability to comply with study procedures and follow-up requirements.
  • Age: Age 18 to 75 years (inclusive).
  • Planned Surgery: Planned to undergo radical cystectomy (RC) with lymph node dissection (LND).
  • Clinical Stage: Clinical stage T2-T4aNxM0, as assessed by CT, MRI, or PET-CT.
  • 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).
  • Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
  • 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
  • Cardiac Function: New York Heart Association (NYHA) class < 3.
  • 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

：

  • Receipt of live attenuated vaccine within 4 weeks prior to enrollment or planned receipt during the study period.
  • Receipt of systemic chemotherapy, or anti-PD-1, anti-PD-L1, or HER2-targeted therapy within the past 6 months.
  • Known hypersensitivity to gemcitabine, disitamab vedotin, toripalimab, or any of their excipients.
  • Active, known, or suspected autoimmune disease.
  • Known history of primary immunodeficiency.
  • History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
  • 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).
  • 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).
  • History of other malignancies within the past 5 years, excluding clinically cured early-stage tumors.
  • Active tuberculosis.

Treatment and study plan

Gemcitabine

Drug

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).

Toripalimab

Drug

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).

Disitamab Vedotin (RC48)

Drug

On Day 1 of each neoadjuvant therapy cycle, a dose of 2 mg/kg is administered via intravenous infusion over 30-60 minutes.

Radical Cystectomy

Procedure

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.

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

Other outcomes

  1. 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.

  2. 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.

  3. 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Zhiquan Hu, M.D.

CONTACT

[email protected]

13971656164

Sponsors and collaborators

Lead sponsor

Zhiquan Hu

Other

Collaborators

  • Tongji Hospital

Registry information

Official study title

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

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Jul 9, 2026
Registry last updated
Jul 9, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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