Immediate Versus Deferred Cytoreductive Nephrectomy With Ipilimumab/Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: A Multicenter, Randomized, Open-Label, Phase III Trial
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 172
- 主要终点
- Progression-Free Survival (PFS) assessed by RECIST version 1.1
研究概览
简要总结
The goal of this clinical trial is to learn whether the timing of surgery (cytoreductive nephrectomy) improves outcomes when combined with immunotherapy (ipilimumab and nivolumab) in adults with metastatic clear cell renal cell carcinoma.
The main questions this study aims to answer are:
- Does upfront (immediate) surgery before immunotherapy improve survival compared to delayed surgery after immunotherapy?
- What medical problems (side effects or complications) occur with each treatment sequence?
- How do the two strategies affect quality of life?
Researchers will compare two groups:
- Upfront surgery group: Participants will have surgery first, then receive 4 cycles of ipilimumab/nivolumab, followed by nivolumab maintenance.
- Deferred surgery group: Participants will receive 4 cycles of ipilimumab/nivolumab first, then surgery, followed by nivolumab maintenance.
Participants will:
- Be randomly assigned to one of the two groups
- Undergo regular clinic visits, imaging tests, and blood collections for safety and biomarker studies
- Be followed for 15 months to check disease progression, complications, survival, and quality of life
This trial will help determine the best timing for surgery in the era of immunotherapy and provide evidence for improved treatment strategies for patients with metastatic kidney cancer
详细描述
This is a multicenter, randomized, open-label phase III trial designed to evaluate the optimal timing of cytoreductive nephrectomy (CN) in patients with synchronous metastatic clear cell renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors.
Although CN has historically been considered standard in mRCC, the timing of surgery (immediate vs deferred) remains controversial, particularly after the introduction of immune checkpoint blockade. Recent retrospective studies and meta-analyses suggest potential survival benefits of deferred CN following systemic therapy, but high-level prospective evidence is lacking.
In this study, participants with intermediate or poor IMDC risk mRCC will be randomized into two groups:
- Upfront CN arm: Patients undergo immediate CN followed by 4 cycles of ipilimumab plus nivolumab (Ipi/Nivo) and then nivolumab maintenance.
- Deferred CN arm: Patients receive 4 cycles of Ipi/Nivo induction first, followed by CN, and then nivolumab maintenance.
The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity, radiologic response, rate of unresectable tumors in the deferred group, impact of CN on early progression, surgical outcomes, and quality of life. Exploratory endpoints include biomarker studies using peripheral blood mononuclear cells (PBMCs) to characterize responders vs non-responders to Ipi/Nivo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following:
- •Age ≥ 19 years (male or female).
- •Histologically confirmed synchronous metastatic clear cell renal cell carcinoma.
- •ECOG performance status 0-
- •At least one measurable metastatic lesion (per RECIST v1.1).
- •Primary renal tumor considered surgically resectable.
- •IMDC intermediate- or poor-risk classification.
- •Estimated life expectancy > 3 months.
- •Ability to understand and voluntarily sign informed consent.
排除标准
- •Prior systemic therapy for metastatic RCC.
- •History of another malignancy diagnosed or treated within 2 years (except for cured non-melanoma skin cancer or in-situ cancers).
- •Significant comorbid conditions making participation inappropriate, such as:
- •Moderate to severe cardiovascular, cerebrovascular, pulmonary, or hepatic disease.
- •History or suspicion of autoimmune disease incompatible with immune checkpoint inhibitor therapy.
- •Requirement for systemic corticosteroid therapy >10 mg/day prednisone equivalent, or other immunosuppressive drugs.
- •Any other condition judged by the investigator to make the patient unsuitable for trial participation.
研究组 & 干预措施
Upfront Cytoreductive Nephrectomy (CN)
Participants will undergo immediate cytoreductive nephrectomy. About 4 weeks after surgery, they will receive induction therapy with ipilimumab plus nivolumab for 4 cycles, followed by maintenance nivolumab. Regular assessments of progression, perioperative complications, safety, and quality of life will be performed for 15 months.
干预措施: Cytoreductive Nephrectomy (Procedure)
Deferred Cytoreductive Nephrectomy (CN)
Participants will first receive 4 cycles of ipilimumab plus nivolumab induction therapy. After reassessment, they will undergo deferred cytoreductive nephrectomy, followed by maintenance nivolumab. Safety, perioperative complications, progression, and quality of life will be evaluated regularly for 15 months
干预措施: Cytoreductive Nephrectomy (Procedure)
Deferred Cytoreductive Nephrectomy (CN)
Participants will first receive 4 cycles of ipilimumab plus nivolumab induction therapy. After reassessment, they will undergo deferred cytoreductive nephrectomy, followed by maintenance nivolumab. Safety, perioperative complications, progression, and quality of life will be evaluated regularly for 15 months
干预措施: Ipilimumab plus Nivolumab (Drug)
Upfront Cytoreductive Nephrectomy (CN)
Participants will undergo immediate cytoreductive nephrectomy. About 4 weeks after surgery, they will receive induction therapy with ipilimumab plus nivolumab for 4 cycles, followed by maintenance nivolumab. Regular assessments of progression, perioperative complications, safety, and quality of life will be performed for 15 months.
干预措施: Ipilimumab plus Nivolumab (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) assessed by RECIST version 1.1
时间窗: Up to 15 months after treatment initiation
Time from randomization to first documented disease progression or death from any cause, whichever occurs first. Disease progression will be assessed according to RECIST version 1.1 criteria and clinical evaluation.
次要结局
- Rate of Unresectable Tumors in the Deferred Arm(At the time of planned deferred cytoreductive nephrectomy)
- Early Disease Progression Rate Within 4 Weeks Post-Nephrectomy(Within 4 weeks of cytoreductive nephrectomy)
- Overall Survival (OS)(Up to 15 months after treatment initiation)
- Radiologic Tumor Response Rate Assessed by RECIST v1.1(At baseline, at 12 weeks (after 4 cycles of ipilimumab/nivolumab induction therapy), and every 12 weeks thereafter up to 15 months)
- Health Utility Score Assessed by EQ-5D-5L(Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months)
- Rate and Severity of Perioperative Complications Assessed by Clavien-Dindo Classification(Within 90 days after cytoreductive nephrectomy)
- Quality of Life Assessed by FACT-Kidney Symptom Index 15-item (FKSI-15)(Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months)
- Quality of Life Assessed by EORTC QLQ-C30(Baseline, at 12 weeks (after 4 cycles of therapy), and every 12 weeks thereafter up to 15 months)
- Rate and Severity of Perioperative Adverse Events Assessed by CTCAE v4.0(Within 90 days after cytoreductive nephrectomy)
- Rate of Open vs Minimally Invasive Surgical Approach(At time of cytoreductive nephrectomy)
- Extent of Surgery (e.g., Radical vs Partial Nephrectomy; Lymphadenectomy Yes/No)(At time of cytoreductive nephrectomy)
研究者
Chang Wook Jeong
Professor
Seoul National University Hospital