The Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma in Immuno-oncology Era: SEVURO-CN Trial

Study Overview
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Brief Summary
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BACKGROUND: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been questioned and remains undetermined in the immuno-oncology era. Results from the two randomized trials, CARMENA and SURTIME, have questioned the role and timing of the surgery in these patients, however, these trials have only used the targeted therapy, sunitinib. With the advent of more effective systemic therapies including immune checkpoint inhibitors (ICIs), the role of surgical therapy should be reexamined. RATIONALE: The therapeutic effects of ICIs have demonstrated improved oncological outcomes compared to sunitinib. The updated results reported the beneficial role of upfront and deferred CN approach for selected patients. No studies have formally investigated the role of CN in the immune-oncology era where combinatorial use of CN plus ICIs might be beneficial. HYPOTHESIS: Upfront or deferred CN will improve oncological outcomes (overall survival, and progression free survival) in patients with synchronous mRCC and ≤3 IMDC risk features compared to immune checkpoint inhibitors (nivolumab plus ipilimumab combination) alone. This is an open, randomized, multicenter comparison trial, designed to evaluate the effect of the potential role of CN in combination with immunotherapy in mRCC patients with IMDC intermediate and poor risk.

Official Title
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The Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma in Immuno-oncology Era: SEVURO-CN Trial

Conditions
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Kidney Cancer, Clear Cell Renal Cell Carcinoma Metastatic, Synchronous Neoplasm

Intervention / Treatment
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* Procedure: Cytoreductive nephrectomy±metastasectomy
* Procedure: Cytoreductive nephrectomy±metastasectomy
* Other: Human-derived materials sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Core needle biopsy proven metastatic renal cell carcinoma - clear cell histologic subtypes only acceptable. Synchronous metastatic renal cell carcinoma with the primary tumor present in the kidney. Patient must be willing to provide their human-derived materials. Age ≥19. Signed written informed consent obtained prior to any study specific procedures. Patient must be willing and able to comply with the protocol. Measurable disease as per RECIST v 1.1 Life expectancy of greater than 4 months. Patients with more than one prognostic factor by the International Metastatic RCC Database Consortium (IMDC) criteria (intermediate- or poor-risk group). Patients for which Nivolumab/Ipilimumab considered indicated according to the recommendations by the national health authorities. The prescription of nivolumab/ipilimumab in the circumstances of the study is considered as a standard treatment. Karnofsky Performance status ≥70 Females with a negative serum pregnancy test unless childbearing potential can be otherwise excluded (postmenopausal, hysterectomy or oophorectomy) and not lactating. Fertile women of childbearing potential (<2 years after last menstruation) and men must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgical sterilization). The required laboratory values are as follows: Adequate bone marrow function (Absolute neutrophil count > 1500/mm3, platelets > 100 x 103/µl, hemoglobin > 10.0 g/dL.) International normalized ratio (INR) ≤ 1.2 x upper limit of normal (ULN) Adequate hepatic function (bilirubin ≤ 1.5 x ULN, ALAT ≤ 2.5 x ULN) Adequate kidney function (eGFR > 35 mL/min) Exclusion Criteria: Prior systemic treatment for mRCC Major surgical procedure, open surgical biopsy, or significant traumatic injury within 28 days prior to enrollment Other cancer within 5 years. Clinically significant (i.e active) cardiovascular disease for example cerebrovascular accidents (< 6 months before inclusion), myocardial infarction (< 6 months before inclusion), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure. No symptomatic brain metastasis requiring systemic corticosteroids (> 10 mg daily prednisone equivalent) Recent (within the 30 days prior to inclusion) treatment with another investigational drug or participation in another investigational study. Any active or recent history of a known or suspected autoimmune disease or recent history of a condition that require systemic corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications, excluding inhaled steroids and topical steroids. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, psoriasis not requiring systemic treatment are permitted to enroll. Oral or i.v. antibiotics administered 14 days prior to initiation of systemic therapy. Any positive test for hepatitis B- or C-Virus indicating acute or chronic infection. Known hypersensitivity to monoclonal antibodies. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Patients disagreeing to provide their human-derived materials. Patients not willing and able to comply with the protocol. Vulnerable subjects (such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons). Patients who cannot read and understand the consent form. (illiterate, foreigners, etc.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Upfront cytoreductive nephrectomy<br>Cytoreductive nephrectomy±metastasectomy, followed by induction therapy with nivolumab plus ipilimumab combination and maintenance therapy with nivolumab. | Procedure: Cytoreductive nephrectomy±metastasectomy<br>* Partial or complete nephrectomy by open, laparoscopic, or robotic approach and/or metastasectomy Tumor tissue, blood, urine and stool specimens for translational biomarker research will be sample at baseline, surgery, after induction therapy, and after 3 months of maintenance therapy.<br>* Other names: Human-derived materials sampling;|
| Experimental: Deferred cytoreductive nephrectomy<br>Cytoreductive nephrectomy±metastasectomy after induction therapy with nivolumab plus ipilimumab combination, followed by maintenance therapy with nivolumab. | Procedure: Cytoreductive nephrectomy±metastasectomy<br>* Partial or complete nephrectomy by open, laparoscopic, or robotic approach and/or metastasectomy Tumor tissue, blood, urine and stool specimens for translational biomarker research will be sample at baseline, surgery, after induction therapy, and after 3 months of maintenance therapy.<br>* Other names: Human-derived materials sampling;|
| Active Comparator: No surgery<br>Induction therapy with nivolumab plus ipilimumab combination, followed by maintenance therapy with nivolumab. | Other: Human-derived materials sampling<br>* Tumor tissue, blood, urine and stool specimens for translational biomarker research will be sample at baseline, after induction therapy, and after 3 months of maintenance therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Calculated from the date of inclusion, to the date of death of any cause or censored at the date at last follow-up. | 5 years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | According to the RECIST v1.1 | 5 years follow-up | 
| Objective response rate | According to the RECIST v1.1 | 5 years follow-up | 
| Number of participants with treatment-related adverse events | By Common Terminology Criteria for Adverse Events version 5.0 | 5 years follow-up | 
| Number of participant with surgical morbidity assessed according to the Clavien-Dindo classification of surgical complications | Assessed according to the Clavien-Dindo classification of surgical complications | 5 years follow-up | 
| Tumor infiltrating lymphocytes | Measured by flowcytometry at baseline and after surgery and/or after ICIs compared with OS, PFS, ORR | 5 years follow-up | 
| Genetic mutation profiles of primary tissue | Measured by Next generation sequencing (NGS) methods compared with OS, PFS, and ORR | 5 years follow-up | 
| Genetic mutation profile of circulating tumor DNA | Measured by NGS methods compared with OS, PFS, and ORR | 5 years follow-up | 
| Genetic mutation profile or urine tumor DNA | Measured by NGS methods compared with OS, PFS, and ORR | 5 years follow-up | 
| Profile of gut microbiome | Evaluate the microbiome composition measured by NGS methods compared with OS, PFS, and ORR | 5 years follow-up | 
| Profile of urine microbiome | Evaluate the microbiome composition measured by NGS methods compared with OS, PFS, and ORR | 5 years follow-up |