Neoadjuvant RC48 Plus Gemcitabine in HER2-Expressing MIBC

NCT07693959 | Recruiting Phase 3 DMC

• 1 other identifier: TJ-IRB202605029
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 22

Brief Summary

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.

Conditions

MIBC

Keywords

MIBC; ADC; Toripalimab; RC48; Gemcitabine; Disitamab Vedotin; neoadjuvant therapy

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response (pCR)

  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 Outcomes (1)

• Incidence of Grade ≥3 Treatment-Related Adverse Events (TRAEs) During Neoadjuvant Therapy

  The period starting from the first administration of neoadjuvant therapy and extending through 4 weeks following the last dose.

Other Outcomes (3)

• Clinical Complete Response (cCR)

  Within 1 week after completion of radical cystectomy.

• Event-Free Survival (EFS)

  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)

  From date of first neoadjuvant dose until the date of death from any cause, assessed up to 36 months.

Study Arms (2)

Experimental Arm (RC48 + Gemcitabine)

EXPERIMENTAL

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; Drug: Disitamab Vedotin (RC48); Procedure: Radical Cystectomy

Active Comparator Arm (RC48 + Toripalimab)

ACTIVE COMPARATOR

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: Toripalimab; Drug: Disitamab Vedotin (RC48); Procedure: Radical Cystectomy

Interventions

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).

Experimental Arm (RC48 + Gemcitabine)

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).

Active Comparator Arm (RC48 + Toripalimab)

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.

Active Comparator Arm (RC48 + Toripalimab); Experimental Arm (RC48 + Gemcitabine)

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.

Active Comparator Arm (RC48 + Toripalimab); Experimental Arm (RC48 + Gemcitabine)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Zhiquan Hu: lead
• Tongji Hospital: collaborator

Study Sites (22)

The First Affiliated Hospital of Anhui Medical University

Hefei, Anhui, 230022, China

RECRUITING

Fujian Medical University Union Hospital

Fuzhou, Fujian, 350001, China

RECRUITING

The First Affiliated Hospital of Xiamen University

Xiamen, Fujian, 361003, China

RECRUITING

Zhujiang Hospital of Southern Medical University

Guangzhou, Guangdong, 510280, China

RECRUITING

Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center

Shenzhen, Guangdong, 518117, China

RECRUITING

The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture

Enshi, Hubei, 445000, China

RECRUITING

Huanggang Central Hospital

Huanggang, Hubei, 438000, China

RECRUITING

Huangshi Central Hospital

Huangshi, Hubei, 435000, China

RECRUITING

Jingmen Central Hospital

Jingmen, Hubei, 448000, China

RECRUITING

Jingzhou First People's Hospital

Jingzhou, Hubei, 434000, China

RECRUITING

Jingzhou Central Hospital

Jingzhou, Hubei, 434020, China

RECRUITING

Taihe Hospital

Shiyan, Hubei, 442000, China

RECRUITING

The Central Hospital of Wuhan

Wuhan, Hubei, 430014, China

RECRUITING

Wuhan No.1 Hospital

Wuhan, Hubei, 430022, China

RECRUITING

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430030, China

RECRUITING

Renmin Hospital of Wuhan University

Wuhan, Hubei, 430060, China

RECRUITING

Zhongnan Hospital of Wuhan University

Wuhan, Hubei, 430071, China

RECRUITING

Hubei Cancer Hospital

Wuhan, Hubei, 430079, China

RECRUITING

Xiangyang Central Hospital

Xiangyang, Hubei, 441021, China

RECRUITING

Yichang Central People's Hospital

Yichang, Hubei, 443003, China

RECRUITING

Jiangxi Provincial People's Hospital

Nanchang, Jiangxi, 330006, China

RECRUITING

Shandong Cancer Hospital and Institute

Jinan, Shandong, 250117, China

RECRUITING

Related Publications (2)

• Huang H, Ma W, Zeng X, Liu B, Dai H, Zhou G, Wan J, Zhang Y, Hu Z, Yang C. Efficacy and Safety of Disitamab Vedotin Combined with Gemcitabine as Neoadjuvant Therapy in Muscle-invasive Bladder Cancer: An Open-label, Multicenter, Single-arm, Phase 2 Trial. Eur Urol. 2025 Nov 4:S0302-2838(25)04768-2. doi: 10.1016/j.eururo.2025.10.009. Online ahead of print.

  PMID: 41193372 RESULT

• Sheng X, Yan X, Wang L, Shi Y, Yao X, Luo H, Shi B, Liu J, He Z, Yu G, Ying J, Han W, Hu C, Ling Y, Chi Z, Cui C, Si L, Fang J, Zhou A, Guo J. Open-label, Multicenter, Phase II Study of RC48-ADC, a HER2-Targeting Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma. Clin Cancer Res. 2021 Jan 1;27(1):43-51. doi: 10.1158/1078-0432.CCR-20-2488. Epub 2020 Oct 27.

  PMID: 33109737 RESULT

MeSH Terms

Interventions

Gemcitabine; toripalimab; disitamab vedotin; RC48 antibody; Cystectomy

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative

Central Study Contacts

Zhiquan Hu, M.D.

CONTACT

13971656164; huzhiquan2000@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical professor

Study Record Dates

• First Submitted: June 28, 2026
• First Posted: July 9, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029
• Last Updated: July 9, 2026

Record last verified: 2026-06

Locations

CN (22)