Metastatic Renal Cell Carcinoma ( mRCC)
Conditions
Keywords
Metastatic Renal Cell Carcinoma, Immune Checkpoint Inhibitor, Cytoreductive Nephrectomy, Progression-Free Survival, Randomized Clinical Trial
Brief summary
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
Detailed description
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. Patients will be followed for 15 months after treatment initiation, with regular imaging, clinical assessments, and laboratory monitoring. Approximately 172 patients across 12 institutions in Korea will be enrolled. The results of this trial are expected to establish high-level evidence regarding the role and optimal timing of CN in mRCC, improve clinical decision-making, and provide guidance for treatment strategies in the immuno-oncology era
Interventions
Participants will receive 4 cycles of ipilimumab combined with nivolumab as induction therapy, followed by nivolumab maintenance depending on randomization schedule (before or after surgery).
PROCEDURECytoreductive Nephrectomy
Surgical removal of the primary kidney tumor (cytoreductive nephrectomy), performed either upfront (before systemic therapy) or deferred (after 4 cycles of ipilimumab/nivolumab induction), depending on randomization arm.
Sponsors
Seoul National University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 0-1. * 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) assessed by RECIST version 1.1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate and Severity of Perioperative Complications Assessed by Clavien-Dindo Classification | Within 90 days after cytoreductive nephrectomy | Proportion of patients experiencing perioperative complications graded using the Clavien-Dindo classification (Grades I-V). |
| Rate and Severity of Perioperative Adverse Events Assessed by CTCAE v4.0 | Within 90 days after cytoreductive nephrectomy | Severity of postoperative adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Grade 1-5). |
| 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 | Rate of complete response (CR) and partial response (PR) to ipilimumab/nivolumab, assessed using RECIST version 1.1. |
| Rate of Unresectable Tumors in the Deferred Arm | At the time of planned deferred cytoreductive nephrectomy | Proportion of participants in the deferred arm with tumors deemed unresectable at surgery. |
| Early Disease Progression Rate Within 4 Weeks Post-Nephrectomy | Within 4 weeks of cytoreductive nephrectomy | Proportion of patients showing disease progression (PD) within 4 weeks after surgery in both arms. |
| Overall Survival (OS) | Up to 15 months after treatment initiation | Time from randomization to death from any cause. |
| Extent of Surgery (e.g., Radical vs Partial Nephrectomy; Lymphadenectomy Yes/No) | At time of cytoreductive nephrectomy | Surgical extent categories documented at time of surgery. |
| 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 measured using the Functional Assessment of Cancer Therapy - Kidney Symptom Index 15-item (FKSI-15) questionnaire. The total score ranges from 0 to 60, with higher scores indicating better quality of life and fewer kidney cancer-related symptoms. |
| 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 | Patient-reported outcomes evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Scores for each domain range from 0 to 100. |
| 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 | Health status measured using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire. The EQ-5D-5L utility index score typically ranges from \<0 (health states worse than death) to 1 (full health), with higher scores representing better overall health status. The EQ-VAS records self-rated health on a 0-100 scale, where higher scores indicate better perceived health. |
| Rate of Open vs Minimally Invasive Surgical Approach | At time of cytoreductive nephrectomy | Proportion of surgeries performed using open or minimally invasive techniques. |
Contacts
Primary ContactChang Wook Jeong, MD, PhD
Backup ContactJang Hee Han, MD, PhD
Outcome results
None listed