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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Muscle Invasive Bladder Cancer (MIBC)
• Intervention / Treatment: Drug: Zanidatamab; Drug: Tislelizumab; Drug: Cisplatin; Drug: Gemcitabine; Drug: Nab-paclitaxel

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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shaoxing Zhu, MD; Phone Number: 86-18758872716; Email: zsx2005@126.com

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Recruiting
      • Fujian Medical University Union Hospital
      • Contact: Shaoxing Zhu, MD; Phone Number: 86-18758872716; Email: zsx2005@126.com
    • Fuzhou, Fujian, China, 350001
      • Recruiting
      • Fujian Provincial Hospital Affiliated to Fuzhou University
      • Contact: Qingguo Zhu; Phone Number: 86-13115910047; Email: zuqinguo@163.com
    • Putian, Fujian, China, 351106
      • Recruiting
      • Affiliated Hospital of Putian University
      • Contact: Guowei Lin; Phone Number: 86-13599013301; Email: gwlin98@163.com
    • Quanzhou, Fujian, China, 362002
      • Recruiting
      • Quanzhou First Hospital Affiliated to Fujian Medical University
      • Contact: Changde Fu; Phone Number: 86-15060456767; Email: fucd352@163.com
    • Sanming, Fujian, China, 365099
      • Recruiting
      • Sanming First Hospital
      • Contact: Dongming Lu; Phone Number: 86-18759888086; Email: 944607396@qq.com
    • Xiamen, Fujian, China, 361003
      • Recruiting
      • The First Affi liated Hospital of Xiamen University
      • Contact: Zhun Wu; Phone Number: 86-15880217987; Email: wuzhun2000@163.com
    • Zhangzhou, Fujian, China, 363000
      • Recruiting
      • Zhangzhou Affiliated Hospital to Fujian Medical University
      • Contact: Zhiming Zhuang; Phone Number: 86-13709317819; Email: drzzm@sina.com
  • Jiangxi
    • Nanchang, Jiangxi, China, 330029
      • Recruiting
      • Jiangxi Cancer Hospital
      • Contact: Xinhua Tu; Phone Number: 86-13870628187; Email: Tuxinhua2020@163.com
  • Shandong
    • Jinan, Shandong, China, 250117
      • Recruiting
      • Shandong Cancer Hospital
      • Contact: Jiasheng Bian; Phone Number: 86-15954104097; Email: sdbjs232466@sina.com
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Yijun Shen; Phone Number: 86-13817126663; Email: yijunshen@urocancer.org
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310005
      • Recruiting
      • Zhejiang Cancer Hospital
      • Contact: Jinchao Chen; Phone Number: 86-13758124230; Email: runner421@126.com
    • Wenzhou, Zhejiang, China, 325035
      • Recruiting
      • The First Affiliated Hospital of Wenzhou Medical University
      • Contact: Hang Huang; Phone Number: 86-13738301029; Email: huanghang163@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing to participate, able to provide written informed consent, and able to understand and comply with study requirements and the assessment schedule.
2. Age 18 to 85 years on the date of informed consent.
3. 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%).
4. Availability of TURBT tumor tissue and corresponding pathology report; either fresh surgical tissue or unstained slides may be submitted.
5. HER2-positive: IHC 2+ or 3+.
6. 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.
7. ECOG performance status 0-2.

8. 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

9. 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).
10. 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:

1. Pregnant or breastfeeding women.
2. Uncontrolled infection requiring systemic therapy.
3. Diagnosis of another malignancy within the past 5 years.
4. Major surgery or significant trauma within 28 days prior to enrollment (placement of a vascular access device and TURBT are not considered major surgery).
5. Prior radiotherapy to the bladder for bladder cancer.
6. Active autoimmune disease requiring systemic treatment that, in the investigator's judgment, would affect study therapy.

7. Any of the following cardiovascular criteria:

   1. Cardiac chest pain within ≤28 days before first study dose, defined as moderate pain that limits activities of daily living.
   2. Symptomatic pulmonary embolism within ≤28 days before first study dose.
   3. Any acute myocardial infarction within ≤6 months before first study dose.
   4. Any history of heart failure of New York Heart Association (NYHA) Class III or IV within ≤6 months before first study dose.
   5. Any ventricular arrhythmia of severity ≥ Grade 2 within ≤6 months before first study dose.
   6. Any cerebrovascular accident within ≤6 months before first study dose.
   7. 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.

8. History of acute myocardial infarction or ischemic stroke within 6 months.
9. Human immunodeficiency virus (HIV) infection (i.e., positive antibodies to HIV-1/2), active syphilis infection, or active tuberculosis infection.
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
11. History of interstitial lung disease, non-infectious pneumonitis, or uncontrolled pulmonary disease, including pulmonary fibrosis or acute lung disease.
12. Known hypersensitivity to any study drug.
13. Concurrent participation in another clinical study, unless observational (non-interventional) or in the follow-up phase of an interventional study.
14. Any other condition deemed by the investigator to render the patient ineligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental group

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 for 2-4 cycles, or undergo radical cystectomy without further zanidatamab treatment.; 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 tislelizumab every 3 weeks for 12 cycles.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Complete Response (cCR) Rate	Proportion of participants achieving cCR at the end of neoadjuvant therapy, defined as no evidence of tumor on radiographic imaging, no residual tumor on diagnostic TURBT, and negative urine cytology	At the end of Cycle 4 of neoadjuvant therapy (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-Year Bladder-Intact Disease-Free Survival (BI-DFS)	Percentage of participants who, within 12 months from the first neoadjuvant dose, have no local or regional recurrence, no distant metastasis, no bladder cancer-related death, and have not undergone radical cystectomy	From first neoadjuvant dose to 12 months
2-Year Bladder-Intact Disease-Free Survival (BI-DFS)	Percentage of participants who, within 24 months from the first neoadjuvant dose, have no local or regional recurrence, no distant metastasis, no bladder cancer-related death, and have not undergone radical cystectomy	From first neoadjuvant dose to 24 months
Local Recurrence Free Survival (LRFS)	Time from the first neoadjuvant dose to local recurrence or death from any cause; participants without an event will be censored at last follow-up	From first neoadjuvant dose until event, assess up to 3 years
Distant Metastasis Free Survival (DMFS)	Time from the first neoadjuvant dose to distant metastasis or death from any cause; participants without an event will be censored at last follow-up	From first neoadjuvant dose until event, assess up to 3 years
Overall Survival (OS)	Time from the first neoadjuvant dose to death from any cause; participants alive at analysis will be censored at last follow-up.	From first neoadjuvant dose until death, assess up to 3 years
Safety and Adverse Events	Summary of study drug exposure (duration and dose) and adverse events	From first dose through last follow-up, assess up to 3 years
Quality of Life Assessed by EORTC QLQ-C30	To assess changes in overall and cancer-specific quality of life (QoL) from baseline to post-treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) in patients with HER2-positive MIBC receiving neoadjuvant and selective bladder-preserving therapy.	From baseline through last follow-up, assess up to 3 years
Quality of Life Assessed by FACT-BI	To assess changes in bladder cancer-specific quality of life (QoL) from baseline to post-treatment using the Functional Assessment of Cancer Therapy-Bladder (FACT-BI) questionnaire in patients with HER2-positive MIBC receiving neoadjuvant and selective bladder-preserving therapy.	From baseline through last follow-up, assess up to 3 years

Collaborators and Investigators

• Sponsor: Fujian Medical University Union Hospital
• Collaborators: BeiGene

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: September 26, 2025
• First Submitted That Met QC Criteria: December 8, 2025
• First Posted (Actual): December 22, 2025

Study Record Updates

• Last Update Posted (Actual): December 22, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Platinum Compounds; Gemcitabine; Cisplatin; 130-nm albumin-bound paclitaxel; zanidatamab; tislelizumab
• Other Study ID Numbers: HARBOR-II-2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No