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NCT Number: NCT07741448

Neoadjuvant Gemcitabine Plus Trastuzumab Rezetecan in HER2-positive UTUC

Upper tract urothelial carcinoma (UTUC) carries a poor prognosis, with conventional GC (gemcitabine plus cisplatin) regimens achieving only a 19% pathological complete response (pCR) rate in the neoadjuvant setting. Antibody-drug conjugates (ADCs) have shown promising results in advanced urothelial carcinoma, Meanwhile the clinical application of traditional cisplatin-based chemotherapy is associated with significant limitations. Therefore, exploring the efficacy and safety of Trastuzumab Rezetecan (an anti-HER2 ADC) combined with gemcitabine in UTUC is of considerable importance.

This trial will enroll patients with HER2 2-3+ UTUC. After pathological diagnosis, patients will receive intravenous infusions of gemcitabine and Trastuzumab Rezetecan. The treatment regimen consists of a 21-day cycle: 4 cycles of neoadjuvant therapy, followed by 2 cycles of adjuvant therapy for patients who do not achieve pCR (total of 6 cycles). For patients with suboptimal pathological downstaging after surgery (≥ypT3 or ypN+), combination with immune checkpoint inhibitors (ICIs) is recommended.

During the neoadjuvant period, adverse events will be closely monitored. Regular imaging and follow-up assessments will be performed, and events such as disease recurrence, progression, and their corresponding time points will be documented.

The primary endpoint is pCR rate. Secondary endpoints include adverse events during the neoadjuvant period, event-free survival (EFS), overall survival (OS).

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Key information

Conditions

UTUC

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Huanggang Central Hospital, Huanggang, Hubei, China

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • The subject voluntarily participates in the study, provides written informed consent, and is able to comply with study procedures and follow-up visits.
  • Aged between 18 and 75 years.
  • Patients diagnosed with upper tract urothelial carcinoma (UTUC) who are candidates for radical nephroureterectomy with bladder cuff excision.
  • Clinical stage T1N0M0 - T2-T4aN1M0 (evaluated by CT/MRI/PET-CT).
  • Histopathology confirms urothelial carcinoma as the predominant component; IHC testing shows HER2 expression of 2+ to 3+.
  • ECOG performance status ≤ 2.
  • Laboratory parameters meet all of the following criteria:
  • Absolute neutrophil count ≥ 1.5 × 10⁹/L
  • Platelets ≥ 100 × 10⁹/L; hemoglobin ≥ 90 g/L
  • Total bilirubin ≤ 1.5 × ULN
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≤ 2.5 × ULN; serum creatinine ≤ 3 × ULN
  • Cardiac function: New York Heart Association (NYHA) classification < Grade III.

Exclusion criteria

  • Received live attenuated vaccines within 4 weeks prior to enrollment or plan to receive such vaccines during the study.
  • Received systemic chemotherapy, anti-PD-1/PD-L1 agents, or HER2-targeted therapy within the previous 6 months.
  • Known hypersensitivity to gemcitabine, Trastuzumab Rezetecan, or any of their excipients.
  • Active, known or suspected autoimmune disease.
  • Known history of primary immunodeficiency.
  • Known history of solid organ allotransplantation or allogeneic hematopoietic stem cell transplantation.
  • Female patients who are pregnant or breastfeeding.
  • Untreated acute or chronically active hepatitis B or hepatitis C infection. Patients receiving antiviral therapy may be considered eligible at the investigator's discretion with ongoing viral load monitoring.
  • Uncontrolled concurrent illnesses, including but not limited to:
  • HIV infection (positive HIV antibody).
  • Severe active infection with inadequate clinical control.
  • Evidence of severe or uncontrolled systemic disease (e.g., severe psychiatric or neurological disorders, epilepsy or dementia; unstable or decompensated respiratory, cardiovascular, hepatic or renal disease; uncontrolled hypertension defined as CTCAE Grade ≥2 hypertension despite medical treatment).
  • Active bleeding, newly diagnosed thromboembolic disease requiring therapeutic anticoagulation, or bleeding diathesis.
  • Diagnosis of another malignant tumor within the past 5 years.
  • Active tuberculosis

Treatment and study plan

Trastuzumab Rezetecan

Drug

Gemcitabine 1000 mg/m² is given via intravenous infusion, followed by intravenous administration of trastuzumab rezetecan 4.8 mg/kg 3 hours thereafter. The treatment consists of 4 cycles in total with a 21-day cycle interval. Patients without pathological complete response (pCR) will receive 2 cycles of adjuvant therapy

Gemcitabine

Drug

Gemcitabine 1000 mg/m² is given via intravenous infusion, followed by intravenous administration of trastuzumab rezetecan 4.8 mg/kg 3 hours thereafter. The treatment consists of 4 cycles in total with a 21-day cycle interval. Patients without pathological complete response will receive 2 cycles of adjuvant therapy

Radical nephroureterectomy

Procedure

After completing four cycles of neoadjuvant therapy, patients undergo radical nephroureterectomy (RNU). The surgical resection typically includes:

  • The affected kidney (including the perirenal fat capsule); 2) The entire ureter from the renal pelvis to the intramural segment; 3) A bladder cuff around the ureteral orifice; 4) In addition, ipsilateral regional lymph node dissection (e.g., hilar, para-aortic, and paracaval nodes) may be performed depending on tumor stage and clinical indication.

Primary outcomes

  1. Pathological Complete Response (pCR)

    Time frame: Within 1 week after completion of radical nephroureterectomy

    Defined as the absence of residual viable tumor cells (ypT0N0) in RNU specimens. Assessed post surgery. Method: A central pathology review committee performs review of slides from all eligible patients. 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 outcomes

  1. Treatment Related Adverse Events During Neoadjuvant Therapy

    Time frame: The period starting from the first administration of neoadjuvant therapy and extending through 4 weeks following the last dose.

    The patients will be evaluated according to CTCAE 5.0 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 conducts centralized review of all Grade ≥3 events for final adjudication.

Other outcomes

  1. Event-Free Survival

    Time frame: From date of first neoadjuvant dose until the date of first documented events above, whichever came first, assessed up to 36 months

    Defined as time from neoadjuvant start to first occurrence of: disease progression (local/regional recurrence, distant metastasis, or definite clinical progression); death from any cause; initiation of new anti-cancer therapy due to progression or toxicity. Censored at last known event-free assessment. Assessed at scheduled visits. Method: A central follow-up unit conducts structured symptom queries; any suspected event triggers medical evaluation. All potential event materials (imaging, records, symptom logs, death certificates) are submitted to an independent CEC for adjudication of event and date, final for analysis.

  2. Overall Survival

    Time frame: From date of first neoadjuvant dose until the date of death from any cause, assessed up to 36 months.

    Defined as time from neoadjuvant start to death from any cause. Assessed at scheduled visits. Method: Central follow-up unit collects objective death documents from multiple sources. The independent CEC reviews all documents, verifies and adjudicates the exact date of death, which serves as the final basis for OS calculation.

Study contacts

Contact information is provided by the study sponsor or research team.

Chunguang Yang, M.D.

CONTACT

[email protected]

86+13871084024

Zhiquan Hu, M.D.

CONTACT

[email protected]

86+13971656164

Sponsors and collaborators

Lead sponsor

Zhiquan Hu

Other

Registry information

Official study title

An Open-label, Single-arm, Multicenter Phase II Clinical Study to Evaluate Neoadjuvant Gemcitabine Combined With Trastuzumab Rezetecan in HER2-positive Upper Tract Urothelial Carcinoma

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Aug 3, 2026
Registry last updated
Aug 3, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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