Neoadjuvant Gemcitabine Plus Trastuzumab Rezetecan in HER2-positive UTUC

NCT07741448 | Recruiting Phase 2 DMC

• 1 other identifier: [226] LSZ (S023) No
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 10

Brief Summary

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).

Conditions

UTUC

Keywords

Trastuzumab Rezetecan; Gemcitabine; UTUC; neoadjuvant therapy

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response (pCR)

  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.

  Within 1 week after completion of radical nephroureterectomy

Secondary Outcomes (1)

• Treatment Related Adverse Events During Neoadjuvant Therapy

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

Other Outcomes (2)

• Event-Free Survival

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

• Overall Survival

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

Study Arms (1)

Trastuzumab Rezetecan plus Gemcitabine Group

EXPERIMENTAL

Drug: Trastuzumab Rezetecan; Drug: Gemcitabine; Procedure: Radical nephroureterectomy

Interventions

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

Trastuzumab Rezetecan plus Gemcitabine Group

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

Trastuzumab Rezetecan plus Gemcitabine Group

Radical nephroureterectomy PROCEDURE

After completing four cycles of neoadjuvant therapy, patients undergo radical nephroureterectomy (RNU). The surgical resection typically includes: 1\) 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.

Trastuzumab Rezetecan plus Gemcitabine Group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Zhiquan Hu: lead

Study Sites (10)

Huanggang Central Hospital

Huanggang, Hubei, 438000, China

RECRUITING

Jingzhou Central Hospital

Jingzhou, Hubei, 434020, China

RECRUITING

Taihe Hospital

Shiyan, Hubei, 442000, China

RECRUITING

The Central Hospital of Wuhan

Wuhan, Hubei, 430014, China

RECRUITING

Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technolog

Wuhan, Hubei, 430030, China

RECRUITING

Renmin Hospital of Wuhan University

Wuhan, Hubei, 430060, China

RECRUITING

Zhongnan Hospital of Wuhan University

Wuhan, Hubei, 430071, China

RECRUITING

Hubei Cancer Hospital

Wuhan, Hubei, 430079, China

RECRUITING

Xiangyang Central Hospital

Xiangyang, Hubei, 441021, China

RECRUITING

Yichang Central People's Hospital

Yichang, Hubei, 443003, China

RECRUITING

MeSH Terms

Interventions

Gemcitabine

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Central Study Contacts

Zhiquan Hu, M.D.

CONTACT

86+13971656164; huzhiquan2000@163.com

Chunguang Yang, M.D.

CONTACT

86+13871084024; cgyang-hust@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical professor

Study Record Dates

• First Submitted: July 29, 2026
• First Posted: August 3, 2026
• Study Start (Estimated): August 15, 2026
• Primary Completion (Estimated): August 15, 2028
• Study Completion (Estimated): August 15, 2029
• Last Updated: August 3, 2026

Record last verified: 2026-07

Locations

CN (10)