Neoadjuvant Zanidatamab + Tislelizumab + Chemotherapy for Selective Bladder Preservation in HER2-Positive MIBC
Selective Bladder Preservation After Neoadjuvant Zanidatamab Combined With Tislelizumab and Chemotherapy in Patients With HER2-Positive Muscle-Invasive Bladder Cancer: A Multicenter Study
Fujian Medical University Union Hospital
25 participants
Oct 25, 2025
INTERVENTIONAL
Conditions
Summary
This is a multicenter, open-label, prospective, single-arm, phase II study designed to evaluate the efficacy and safety of neoadjuvant zanidatamab combined with tislelizumab and chemotherapy, followed by selective bladder preservation, in patients with HER2-positive muscle-invasive bladder cancer (MIBC) staged cT2-4aN0-1M0.
Eligibility
Inclusion Criteria11
- Willing to participate, able to provide written informed consent, and able to understand and comply with study requirements and the assessment schedule.
- Age 18 to 85 years on the date of informed consent.
- Residual disease after TURBT; histologically confirmed urothelial carcinoma of the bladder staged cT2-T4aN0-1M0 per AJCC 8th edition by histology and imaging. For mixed histology, urothelial carcinoma must be predominant (≥50%).
- Availability of TURBT tumor tissue and corresponding pathology report; either fresh surgical tissue or unstained slides may be submitted.
- HER2-positive: IHC 2+ or 3+.
- No prior anti-HER2-directed therapy (including but not limited to HER2 antibodies, HER2-targeting ADCs, or HER2-targeted TKIs) and no prior PD-(L)1 therapy.
- ECOG performance status 0-2.
- Adequate organ function based on screening labs obtained ≤14 days before enrollment:
- a. For the following counts, no growth-factor support within 14 days prior to sample collection: i. Absolute neutrophil count ≥ 1.5 × 10\^9/L ii. Platelets ≥ 100 × 10\^9/L iii. Hemoglobin ≥ 90 g/L b. INR or aPTT ≤ 1.5 × upper limit of normal (ULN) c. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for Gilbert syndrome or isolated indirect hyperbilirubinemia) d. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN
- Women of childbearing potential must have a negative urine or serum pregnancy test within ≤7 days before enrollment and agree to use highly effective contraception during the study and for ≥120 days after the last dose of zanidatamab, tislelizumab, or chemotherapy (whichever occurs later).
- Non-sterilized men must agree to use highly effective contraception during the study and for ≥120 days after the last dose of zanidatamab, tislelizumab, or chemotherapy (whichever occurs later).
Exclusion Criteria23
- Pregnant or breastfeeding women.
- Uncontrolled infection requiring systemic therapy.
- Diagnosis of another malignancy within the past 5 years.
- Major surgery or significant trauma within 28 days prior to enrollment (placement of a vascular access device and TURBT are not considered major surgery).
- Prior radiotherapy to the bladder for bladder cancer.
- Active autoimmune disease requiring systemic treatment that, in the investigator's judgment, would affect study therapy.
- Any of the following cardiovascular criteria:
- Cardiac chest pain within ≤28 days before first study dose, defined as moderate pain that limits activities of daily living.
- Symptomatic pulmonary embolism within ≤28 days before first study dose.
- Any acute myocardial infarction within ≤6 months before first study dose.
- Any history of heart failure of New York Heart Association (NYHA) Class III or IV within ≤6 months before first study dose.
- Any ventricular arrhythmia of severity ≥ Grade 2 within ≤6 months before first study dose.
- Any cerebrovascular accident within ≤6 months before first study dose.
- Corrected QT interval (QTc by Fridericia): ≥470 msec for women or ≥450 msec for men.
- i. Note: If the initial ECG shows QTc \>450 msec (men) or \>470 msec (women), a follow-up ECG should be performed to confirm.
- h) Left ventricular ejection fraction (LVEF) ≤50% by multigated acquisition (MUGA) scan or echocardiography (ECHO). The same modality used at baseline must be used for follow-up assessments.
- History of acute myocardial infarction or ischemic stroke within 6 months.
- Human immunodeficiency virus (HIV) infection (i.e., positive antibodies to HIV-1/2), active syphilis infection, or active tuberculosis infection.
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- History of interstitial lung disease, non-infectious pneumonitis, or uncontrolled pulmonary disease, including pulmonary fibrosis or acute lung disease.
- Known hypersensitivity to any study drug.
- Concurrent participation in another clinical study, unless observational (non-interventional) or in the follow-up phase of an interventional study.
- Any other condition deemed by the investigator to render the patient ineligible.
Interventions
Zanidatamab (1,800 mg for patients \<70 kg or 2,400 mg for patients ≥70 kg, administered intravenously every 3 weeks) for 4 cycles is given as part of the neoadjuvant regimen. After completion of neoadjuvant therapy, disease status is reassessed. Patients achieving a clinical complete response (cCR) may continue zanidatamab every 3 weeks for 2-4 cycles as part of bladder-preserving treatment; those without cCR may receive radiotherapy or partial cystectomy followed by zanidatamab every 3 weeks for 2-4 cycles, or undergo radical cystectomy without further zanidatamab treatment.
Tislelizumab (200 mg administered intravenously every 3 weeks) is administered for 4 cycles as neoadjuvant therapy. After completion of 4 cycles, disease status is reassessed. Patients achieving a clinical complete response (cCR) may proceed with selective bladder preservation and continue tislelizumab every 3 weeks for 12 cycles; those without cCR may receive radiotherapy or partial cystectomy followed by tislelizumab every 3 weeks for 12 cycles, or undergo radical cystectomy with adjuvant tislelizumab every 3 weeks for 12 cycles.
Cisplatin (70 mg/m² administered intravenously every 3 weeks ) for 4 cycles is included in the neoadjuvant chemotherapy regimen for eligible cisplatin-based chemotherapy.
Gemcitabine (1,000 mg/m² administered intravenously every 3 weeks) for 4 cycles is given as part of the neoadjuvant chemotherapy regimen for eligible cisplatin-based chemotherapy.
Nab-paclitaxel (125 mg/m² administered intravenously every 3 weeks) for 4 cycles is given as part of the neoadjuvant chemotherapy regimen for ineligible or refused cisplatin-based chemotherapy.
Locations(12)
View Full Details on ClinicalTrials.gov
For the most up-to-date information, visit the official listing.
NCT07296705