A Prospective, Multicentre, Single-Arm Phase II Study Evaluating a Response-Adapted Kidney-Preserving Strategy Using Neoadjuvant Disitamab Vedotin Plus Tislelizumab in Patients With HER2-Positive High-Risk Upper Tract Urothelial Carcinoma (DISTINCT-II)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Kidney-Intact Event-Free Survival (KI-EFS) at 1 year
研究概览
简要总结
This is a prospective, multicentre, single-arm phase II study evaluating a response-adapted kidney-preserving strategy in patients with HER2-positive high-risk upper tract urothelial carcinoma (UTUC). Patients will receive neoadjuvant disitamab vedotin plus tislelizumab, followed by response-adapted local treatment, including kidney-sparing surgery or radical nephroureterectomy based on predefined criteria.
The primary objective is to assess whether this multimodal strategy can achieve clinically meaningful oncologic control while preserving renal function, as measured by 1-year kidney-intact event-free survival (KI-EFS). Secondary and exploratory objectives include evaluation of clinical response, survival outcomes, safety, renal function preservation, and longitudinal dynamics of circulating and urinary tumor DNA.
详细描述
This is a prospective, multicentre, single-arm, phase II clinical trial designed to evaluate the efficacy and safety of a response-adapted kidney-preserving treatment strategy in patients with HER2-positive high-risk upper tract urothelial carcinoma (UTUC).
Eligible patients will receive neoadjuvant systemic therapy consisting of disitamab vedotin in combination with tislelizumab administered every 3 weeks for 2-4 cycles. Tumour response will be assessed after two cycles using radiographic evaluation and clinical assessment. Patients demonstrating clinical benefit will proceed to complete induction therapy, followed by comprehensive restaging including imaging, ureteroscopy with biopsy, and urine cytology.
Subsequent local treatment will be determined according to a predefined response-adapted algorithm. Patients meeting protocol-specified criteria will undergo kidney-sparing surgery (KSS), including segmental ureterectomy or endoscopic ablation depending on tumour location and anatomical feasibility. Patients not meeting criteria for KSS will undergo radical nephroureterectomy (RNU).
The primary objective of the study is to determine whether this multimodal strategy can achieve clinically meaningful oncologic control while preserving renal function in a biomarker-selected population.
In addition, longitudinal biospecimen collection will be conducted to evaluate the dynamics of urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) as exploratory biomarkers of treatment response and minimal residual disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is a prospective, open, multiple-center clinical study of renal preservation therapy in high-risk upper urinary tract urothelial carcinoma patients . The study was conducted in accordance with the Good Practice for Quality Control of Clinical Trials for Pharmaceutical Products (GCP). Approximately 20 subjects will be enrolled to evaluate the efficacy and safety of RC48 (2.0 mg/kg intravenously every 3 weeks) combined with Tislelizumab (200mg intravenously every 3 weeks).
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years at the time of informed consent.
- •Histologically confirmed upper tract urothelial carcinoma (UTUC) arising from the renal pelvis or ureter, based on ureteroscopic biopsy.
- •High-risk UTUC, defined by at least one of the following features: Tumour size ≥2 cm; High-grade cytology or biopsy; Radiographic evidence of local invasion (≥cT2); Hydronephrosis; Multifocal disease
- •Clinical stage cT1-T3, N0-N1, M0, based on radiographic assessment.
- •N1 disease is permitted only if lymph nodes are considered resectable.
- •HER2-positive disease, defined as immunohistochemistry (IHC) score of 1+，2+ or 3+ on tumour tissue, assessed according to predefined criteria.
- •At least one measurable lesion according to RECIST version 1.
- •ECOG performance status of 0-1
- •Adequate organ function, including: Hematologic function; Hepatic function; Renal function (no strict upper/lower limit required);
- •Patients must be considered potential candidates for a kidney-preserving treatment strategy, including: Absolute or relative indication for renal preservation (e.g., solitary kidney, baseline renal insufficiency), or Strong preference for kidney preservation after multidisciplinary discussion
- •Ability to understand and willingness to sign written informed consent.
排除标准
- •Evidence of distant metastatic disease (M1).
- •Unresectable or bulky nodal disease (≥N2) not amenable to curative-intent surgery.
- •Prior systemic therapy for urothelial carcinoma, including:Chemotherapy; Immunotherapy; HER2-targeted therapy.
- •Prior radical nephroureterectomy for current disease.
- •Active autoimmune disease requiring systemic treatment within the past 2 years.
- •Current use of immunosuppressive medication, excluding physiologic doses of corticosteroids.
- •Uncontrolled intercurrent illness, including but not limited to: Active infection requiring systemic therapy; Uncontrolled cardiovascular disease; Significant pulmonary disease
- •Known active hepatitis B, hepatitis C, or HIV infection with uncontrolled viral replication.
- •History of another malignancy within the past 5 years, except: Adequately treated basal cell carcinoma; Squamous cell skin cancer; In situ carcinoma.
- •Pregnant or breastfeeding women.
- •Any condition that, in the opinion of the investigator, would interfere with study participation or interpretation of results.
研究组 & 干预措施
Neoadjuvant disitamab vedotin + tislelizumab followed by response-adapted surgery
Drug: Disitamab Vedotin Administered intravenously at 2.0 mg/kg every 3 weeks
Drug: Tislelizumab Administered intravenously at 200 mg every 3 weeks
Procedure: Surgery Kidney-sparing surgery (segmental ureterectomy or endoscopic ablation) or radical nephroureterectomy based on predefined criteria
干预措施: RC48 Combined With Tislelizumab (Drug)
结局指标
主要结局
Kidney-Intact Event-Free Survival (KI-EFS) at 1 year
时间窗: From enrollment to 12 months
KI-EFS is defined as the time from study enrollment to the first occurrence of any of the following events: High-risk recurrence of upper tract urothelial carcinoma (local, regional, or distant), defined according to prespecified clinical or radiographic criteria Death from any cause Conversion to radical nephroureterectomy (RNU) for any reason Patients without an event will be censored at the date of last disease assessment.
次要结局
- Renal Function Preservation(Up to 12 months)
- Kidney-Intact Event-Free Survival at 2 years(Up to 24 months)
- Disease-Free Survival (DFS) Renal Function Preservation(Up to 24 months)
- Clinical Complete Response (cCR) Rate After Induction Therapy(Immediately after Induction Therapy)
- Clinical Complete Response (cCR) Rate After Kidney-Sparing Surgery(1 month after surgery)
- Safety and Tolerability(Up to 90 days post-treatment)