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

Phase 2Not Yet RecruitingNCT07720921

Peking University First Hospital20 enrolled

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.

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

Allocation

Purpose

TREATMENT

Interventions

Neoadjuvant radiotherapyRADIATION

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.

ADC + PD1 monoclonal antibodyDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Pathological complete response rate

Proportion of participants with no residual viable tumor in the surgical specimen, as assessed by pathological evaluation.

Time frame: At radical surgery

Secondary Outcomes

Objective response rate

Rate of participants achieving complete response or partial response based on imaging assessment using RECIST or protocol-defined criteria.

Time frame: 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.

Time frame: through study completion, an average of 1 year"

Disease-free survival

Time from radical surgery to disease recurrence, progression, or death from any cause

Time frame: 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.

Time frame: Up to 3 years after surgery.

Metastasis-free survival

Time from radical surgery to distant metastasis.

Time frame: Up to 3 years after surgery.

Overall survival

Description

Time frame: Up to 3 years after surgery.

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts