MIBC
Conditions
Keywords
MIBC, ADC, Toripalimab, RC48, Gemcitabine, Disitamab Vedotin, neoadjuvant therapy
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.
Interventions
DRUGGemcitabine
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).
DRUGToripalimab
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).
On Day 1 of each neoadjuvant therapy cycle, a dose of 2 mg/kg is administered via intravenous infusion over 30-60 minutes.
PROCEDURERadical 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.
Sponsors
Zhiquan Hu
Tongji Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
Countries
China
Contacts
CONTACTZhiquan Hu, M.D.
Outcome results
None listed