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

Official title

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

Overview

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.

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.

Interventions

• 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

Primary outcome measures

• Pathological complete response rate [Time frame: At radical surgery]

Secondary outcome measures (6)

• Objective response rate [Time frame: At 2 months after initiation of treatment]
• Treatment-related adverse events [Time frame: through study completion, an average of 1 year"]
• Disease-free survival [Time frame: Up to 1 year and 3 years after surgery]
• Local recurrence-free survival [Time frame: Up to 3 years after surgery.]
• Metastasis-free survival [Time frame: Up to 3 years after surgery.]
• Overall survival [Time frame: Up to 3 years after surgery.]

Eligibility criteria

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.

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 · 1 center

• Departmeng of Urology, Peking University First Hospita — Beijing

Identifiers

NCT: NCT07720921 · LUXUS 7.1 · LUXUS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗