Neoadjuvant Zanidatamab + Tislelizumab + Chemotherapy for Selective Bladder Preservation in HER2-Positive MIBC

Official title

Selective Bladder Preservation After Neoadjuvant Zanidatamab Combined With Tislelizumab and Chemotherapy in Patients With HER2-Positive Muscle-Invasive Bladder Cancer: A Multicenter Study

Overview

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.

Detailed description

Eligible patients will receive neoadjuvant therapy with zanidatamab plus tislelizumab in combination with chemotherapy, followed by clinical reassessment. Patients who achieve a clinical complete response (cCR) will continue maintenance therapy with zanidatamab and tislelizumab. Patients who do not achieve cCR may, undergo radiotherapy or partial cystectomy and then continue maintenance zanidatamab plus tislelizumab; alternatively, they may proceed directly to radical cystectomy followed by adjuvant tislelizumab.

Interventions

• Drug Zanidatamab
  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 f
• Drug Tislelizumab
  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 tisl
• Drug Cisplatin
  Cisplatin (70 mg/m² administered intravenously every 3 weeks ) for 4 cycles is included in the neoadjuvant chemotherapy regimen for eligible cisplatin-based chemotherapy.
• Drug Gemcitabine
  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.
• Drug Nab-paclitaxel
  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.

Primary outcome measures

• Clinical Complete Response (cCR) Rate [Time frame: At the end of Cycle 4 of neoadjuvant therapy (each cycle is 21 days)]

Secondary outcome measures (8)

• 1-Year Bladder-Intact Disease-Free Survival (BI-DFS) [Time frame: From first neoadjuvant dose to 12 months]
• 2-Year Bladder-Intact Disease-Free Survival (BI-DFS) [Time frame: From first neoadjuvant dose to 24 months]
• Local Recurrence Free Survival (LRFS) [Time frame: From first neoadjuvant dose until event, assess up to 3 years]
• Distant Metastasis Free Survival (DMFS) [Time frame: From first neoadjuvant dose until event, assess up to 3 years]
• Overall Survival (OS) [Time frame: From first neoadjuvant dose until death, assess up to 3 years]
• Safety and Adverse Events [Time frame: From first dose through last follow-up, assess up to 3 years]
• Quality of Life Assessed by EORTC QLQ-C30 [Time frame: From baseline through last follow-up, assess up to 3 years]
• Quality of Life Assessed by FACT-BI [Time frame: From baseline through last follow-up, assess up to 3 years]

Eligibility criteria

Inclusion criteria

• 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 criteria

• 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.

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 12 centers

• Fujian Medical University Union Hospital — Fuzhou
• Fujian Provincial Hospital Affiliated to Fuzhou University — Fuzhou
• Affiliated Hospital of Putian University — Putian
• Quanzhou First Hospital Affiliated to Fujian Medical University — Quanzhou
• Sanming First Hospital — Sanming
• The First Affi liated Hospital of Xiamen University — Xiamen
• Zhangzhou Affiliated Hospital to Fujian Medical University — Zhangzhou
• Jiangxi Cancer Hospital — Nanchang
• … and 4 more centers

Identifiers

NCT: NCT07296705 · HARBOR-II-2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗