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

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.

Study Overview

• Status: Recruiting
• Conditions: Kidney Cancer; Synchronous Neoplasm; Clear Cell Renal Cell Carcinoma Metastatic
• Intervention / Treatment: Procedure: Cytoreductive nephrectomy±metastasectomy; Other: Human-derived materials sampling

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Won Sik Ham; Phone Number: 02-2228-2310; Email: uroham@yuhs.ac

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Yonsei University Health System, Severance Hospital
    • Contact: Won Sik Ham; Phone Number: 02-2228-2310; Email: uroham@yuhs.ac
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Gangnam Severance Hospital
    • Contact: Kang Su Cho; Phone Number: 82-2-2019-3470; Email: kscho99@yuhs.ac
  • Yongin-si, Korea, Republic of
    • Not yet recruiting
    • Yongin Severance Hospital
    • Contact: Jongchan Kim; Phone Number: 82-10-9364-2395; Email: lumpakcef@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Core needle biopsy proven metastatic renal cell carcinoma - clear cell histologic subtypes only acceptable.
2. Synchronous metastatic renal cell carcinoma with the primary tumor present in the kidney.
3. Patient must be willing to provide their human-derived materials.
4. Age ≥19.
5. Signed written informed consent obtained prior to any study specific procedures.
6. Patient must be willing and able to comply with the protocol.
7. Measurable disease as per RECIST v 1.1
8. Life expectancy of greater than 4 months.
9. Patients with more than one prognostic factor by the International Metastatic RCC Database Consortium (IMDC) criteria (intermediate- or poor-risk group).
10. 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.
11. Karnofsky Performance status ≥70
12. Females with a negative serum pregnancy test unless childbearing potential can be otherwise excluded (postmenopausal, hysterectomy or oophorectomy) and not lactating.
13. 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).

14. 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:

1. Prior systemic treatment for mRCC
2. Major surgical procedure, open surgical biopsy, or significant traumatic injury within 28 days prior to enrollment
3. Other cancer within 5 years.
4. 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.
5. No symptomatic brain metastasis requiring systemic corticosteroids (> 10 mg daily prednisone equivalent)
6. Recent (within the 30 days prior to inclusion) treatment with another investigational drug or participation in another investigational study.
7. 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.
8. Oral or i.v. antibiotics administered 14 days prior to initiation of systemic therapy.
9. Any positive test for hepatitis B- or C-Virus indicating acute or chronic infection.
10. Known hypersensitivity to monoclonal antibodies.
11. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. Patients disagreeing to provide their human-derived materials.
13. Patients not willing and able to comply with the protocol.
14. Vulnerable subjects (such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons).
15. Patients who cannot read and understand the consent form. (illiterate, foreigners, etc.)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Upfront cytoreductive nephrectomy; Cytoreductive nephrectomy±metastasectomy, followed by induction therapy with nivolumab plus ipilimumab combination and maintenance therapy with nivolumab.	Procedure: Cytoreductive nephrectomy±metastasectomy; 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.; Other Names: Human-derived materials sampling
Experimental: Deferred cytoreductive nephrectomy; Cytoreductive nephrectomy±metastasectomy after induction therapy with nivolumab plus ipilimumab combination, followed by maintenance therapy with nivolumab.	Procedure: Cytoreductive nephrectomy±metastasectomy; 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.; Other Names: Human-derived materials sampling
Active Comparator: No surgery; Induction therapy with nivolumab plus ipilimumab combination, followed by maintenance therapy with nivolumab.	Other: Human-derived materials sampling; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yonsei University
• Investigators: Principal Investigator: Won Sik Ham, Department of Urology and Urological Science Institute, Yonsei University College of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2023
• Primary Completion (Estimated): December 27, 2027
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: January 17, 2023
• First Submitted That Met QC Criteria: March 2, 2023
• First Posted (Actual): March 3, 2023

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 19, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Neoplasms, Multiple Primary
• Other Study ID Numbers: 4-2022-1453

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No