Neoadjuvant Gemcitabine Plus Trastuzumab Rezetecan in HER2-positive UTUC

Official 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

Overview

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).

Interventions

• Drug Trastuzumab Rezetecan
  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
• Drug Gemcitabine
  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
• Procedure Radical nephroureterectomy
  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

Primary outcome measures

• Pathological Complete Response (pCR) [Time frame: Within 1 week after completion of radical nephroureterectomy]

Secondary outcome measures (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.]

Eligibility criteria

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

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 · 10 centers

• Huanggang Central Hospital — Huanggang
• Jingzhou Central Hospital — Jingzhou
• Taihe Hospital — Shiyan
• The Central Hospital of Wuhan — Wuhan
• Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Sci — Wuhan
• Renmin Hospital of Wuhan University — Wuhan
• Zhongnan Hospital of Wuhan University — Wuhan
• Hubei Cancer Hospital — Wuhan
• … and 2 more centers

Identifiers

NCT: NCT07741448 · [226] LSZ (S023) No

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗