Neoadjuvant RC48 Plus Gemcitabine in HER2-Expressing MIBC

Official title

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

Overview

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.

Interventions

• 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 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).
• 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.

Primary outcome measures

• Pathological Complete Response (pCR) [Time frame: Within 1 week after completion of radical cystectomy.]

Secondary outcome measures (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.]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 22 centers

• The First Affiliated Hospital of Anhui Medical University — Hefei
• Fujian Medical University Union Hospital — Fuzhou
• The First Affiliated Hospital of Xiamen University — Xiamen
• Zhujiang Hospital of Southern Medical University — Guangzhou
• Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center — Shenzhen
• The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture — Enshi
• Huanggang Central Hospital — Huanggang
• Huangshi Central Hospital — Huangshi
• … and 14 more centers

Publications

• 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
• 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 2 PMID 33109737

Identifiers

NCT: NCT07693959 · TJ-IRB202605029

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗