Neoadjuvant Disitamab Vedotin, Toripalimab, and Radiotherapy for High-risk UTUC ( LUXUS07.1 ) (LUXUS0701)

Efficacy and Safety of Neoadjuvant Disitamab Vedotin, Toripalimab, and Radiotherapy for High-risk Upper Tract Urothelial Carcinoma: A Single-arm, Open Label, Prospective Cohort Study

This is an open-label, single-arm, single-cohort, prospective clinical study evaluating neoadjuvant antibody-drug conjugate therapy combined with immunotherapy and sequential radiotherapy followed by radical surgery in patients with high-risk upper tract urothelial carcinoma (UTUC). Eligible patients will receive neoadjuvant disitamab vedotin (RC48) plus toripalimab, followed by response-guided neoadjuvant radiotherapy and radical nephroureterectomy with bladder cuff excision. The study will assess the safety, feasibility, and preliminary antitumor activity of this multimodal neoadjuvant strategy, with pathological complete response rate as the primary endpoint.

Study Overview

• Status: Not yet recruiting
• Conditions: Neoadjuvant Therapy; Urothelial Carcinoma of the Renal Pelvis and Ureter
• Intervention / Treatment: Radiation: Neoadjuvant radiotherapy; Drug: ADC + PD1 monoclonal antibody

Detailed Description

High-risk UTUC is associated with a substantial risk of recurrence and metastasis after radical surgery. Many patients are unable to tolerate cisplatin-based perioperative chemotherapy because of impaired renal function or treatment-related toxicity. Radiotherapy may improve local control, and low-dose radiation may also modulate the tumor immune microenvironment. Combining an antibody-drug conjugate, immune checkpoint blockade, and sequential radiotherapy before surgery may provide systemic tumor control, enhance local tumor response, and improve pathological downstaging.

This study will enroll patients with resectable, non-metastatic, high-risk UTUC at Peking University First Hospital. Patients will undergo baseline imaging, pathological confirmation, biomarker evaluation, and collection of blood, urine, and tumor specimens. A safety run-in phase of 6 patients will be used to evaluate early safety and dose-limiting toxicities during the first treatment cycle, with special attention to days 7-14. If the safety threshold is met, an additional 14 patients will be enrolled. Interim efficacy assessment will be performed before the penultimate systemic treatment cycle to guide subsequent radiotherapy and surgical planning. Patients will then undergo radical surgery when clinically appropriate and will be followed for recurrence, metastasis, survival, safety, and exploratory molecular endpoints.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: ZUO WEI, Dr; Phone Number: +8618811650832; Email: vivian19980814@126.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Departmeng of Urology, Peking University First Hospita
      • Contact: Xuesong Li, Dr; Phone Number: 86-15801399116; Email: pineneedle@sina.com
      • Contact: WEI ZUO; Email: vivian19980814@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years, male or female.
• Imaging evaluation before treatment excludes distant organ metastasis or other concurrent malignancy and suggests resectable high-risk UTUC.
• Completed pathological biopsy with a clear pathological diagnosis : including puncture biopsy, ureteroscopy and urine cytology, at least one of which is clearly diagnosed as uroepithelial carcinoma, which may include no more than 50% or more proportion of squamous, adenoid, sarcomatoid differentiation and other special differentiation types;
• High-risk features, including muscle-invasive disease, high-grade tumor, multifocal disease, tumor diameter ≥2 cm, hydronephrosis, or regional lymph node involvement.
• HER2 expression by immunohistochemistry 1+ to 3+; PD-L1 expression not restricted.
• Have the willingness to undergo radical surgical treatment and perioperative adjuvant treatment, have good compliance, and be able to co-operate with the treatment and follow-up plan specified by the clinician;
• Postoperative life expectancy of at least 6 months; ECOG score ≤ 2.

Exclusion Criteria:

• Distant metastases or other malignant neoplastic diseases combined with other malignant neoplasms in the same period had been detected at the time of surgery, or the present was a progression after palliative resection of previous epithelial carcinoma of the urothelium;
• History of pelvic and abdominal radiotherapy; history of inflammatory bowel disease; history of systemic chemotherapy;
• Pregnant women or breastfeeding women; or women of childbearing potential who are not using reliable contraception;
• The presence of active infections in those with pre-existing or coexisting haemorrhagic disorders
• clinically significant cardiac disease (e.g., hypertension controlled with medications, unstable angina, New York Heart Association (NYHA) class ≥II congestive heart failure, unstable symptomatic arrhythmias, or class ≥II peripheral vascular disease);
• Psychological, familial, and social factors leading to lack of informed consent.

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: Neoadjuvant ADC, immunotherapy and radiotherapy + radical surgery; Participants in this single cohort will receive neoadjuvant disitamab vedotin (RC48) plus toripalimab, followed by response-guided targeted-volume radiotherapy and radical nephroureterectomy with bladder cuff excision. Surgery is planned approximately 2-4 weeks after completion of the last neoadjuvant treatment, if the patient's clinical condition permits.

Radiation: Neoadjuvant radiotherapy; Patients with a clear pathological diagnosis of high-risk UTUC were treated with a short course of 5 days of naSBRT: radiotherapy irradiation was directed to the primary lesion on the affected side and to the lymphatic drainage area, with a dose of 25 Gy (5 Gy*5 days).The safety of the neoadjuvant radiotherapy dose and regimen can be evaluated by metrological ramping in the initial 5 patients, with subsequent patients following the optimal dose from ramping.; Drug: ADC + PD1 monoclonal antibody; Participants will receive disitamab vedotin (RC48) 2.0 mg/kg intravenously every 2 weeks, on day 1 of each 14-day cycle, for up to 6 cycles, with a maximum safe dose of 120 mg. Participants will also receive toripalimab 3.0 mg/kg intravenously every 2 weeks, on day 1 of each 14-day cycle, for up to 6 cycles. A safety run-in phase will evaluate dose-limiting toxicities. If ≥2 of the first 6 patients experience DLT, the ADC schedule will be adjusted from every 2 weeks for 6 cycles to every 3 weeks for 4 cycles, with continued safety and efficacy monitoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate	Proportion of participants with no residual viable tumor in the surgical specimen, as assessed by pathological evaluation.	At radical surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Rate of participants achieving complete response or partial response based on imaging assessment using RECIST or protocol-defined criteria.	At 2 months after initiation of treatment
Treatment-related adverse events	Incidence and severity of treatment-related adverse events and serious adverse events, graded according to CTCAE.	through study completion, an average of 1 year"
Disease-free survival	Time from radical surgery to disease recurrence, progression, or death from any cause	Up to 1 year and 3 years after surgery
Local recurrence-free survival	Time from radical surgery to local recurrence, including recurrence in the operative bed or regional retroperitoneal lymph nodes.	Up to 3 years after surgery.
Metastasis-free survival	Time from radical surgery to distant metastasis.	Up to 3 years after surgery.
Overall survival	Description	Up to 3 years after surgery.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in plasma circulating tumor DNA (ctDNA) levels	Changes in plasma circulating tumor DNA and association with radiographic response, pathological response, recurrence, and survival.Plasma ctDNA will be assessed using a tumor-informed personalized next-generation sequencing (NGS) assay.	Baseline, 2 months after the first dose, and within 2 weeks after surgery
Urinary tumor DNA dynamics	Changes in urinary tumor DNA and association with tumor burden, molecular residual disease, and clinical outcomes	Baseline, interim assessment during neoadjuvant treatment,post-radiotherapy assessment.

Collaborators and Investigators

• Sponsor: Peking University First Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: June 17, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: UTUC; neoadjuvant radiotherapy; neoadjuvant immunotherapy; prospective cohort; disitamab vedotin; neoadjuvant Antibody-Drug Conjugate
• Additional Relevant MeSH Terms: Therapeutics; Combined Modality Therapy; Neoadjuvant Therapy; arginine decarboxylase
• Other Study ID Numbers: LUXUS 7.1; LUXUS (Other Identifier: Peking university first hospital)

Drug and device information, study documents

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