Deferred Cytoreductive Nephrectomy in Synchronous Metastatic Renal Cell Carcinoma: The NORDIC-SUN-Trial (NORDIC-SUN)

• ClinicalTrials.gov Identifier: NCT03977571
• Recruitment Status: Recruiting
• First Posted: June 6, 2019
• Last Update Posted: June 16, 2022
• Sponsor: Niels Fristrup
• Collaborator: Aarhus University Hospital
• Information provided by (Responsible Party): Niels Fristrup, Aarhus University Hospital

Study Description

Brief Summary:

BACKGROUND: For synchronous metastatic renal cell carcinoma (RCC), surgical resection of the primary tumor in the presence of distant metastases has been the standard of therapy for select patients followed by systemic therapy. In the era of TKIs two randomized trials, CARMENA and SURTIME, have questioned the role and timing of surgery in these patients, results point towards no surgery or a deferred approach.

RATIONALE: The antitumor activity of immune checkpoint blockage (ICB) is more potent than other therapy in mRCC. The deferred cytoreductive nephrectomy approach ensures systemic therapy for all patients, avoid systemic treatment delay, and spare surgery in patients with progressive tumors. Current data only point towards a survival benefit for cytoreductive nephrectomy in intermediate risk patients, but not in poor risk patients

HYPOTHESIS: Deferred cytoreductive nephrectomy after initial nivolumab combined with ipilimumab or a TKI/IO-combination will improve OS in patients with synchronous metastatic RCC and ≤3 IMDC risk features

This is an open, randomized, multicenter comparison trial, designed to evaluate the effect of deferred cytoreductive nephrectomy compared with no surgery following initial nivolumab combined with ipilimumab or a TKI-combination, in mRCC patients with IMDC intermediate and poor risk.

Condition or disease	Intervention/treatment	Phase
Kidney Cancer; Renal Cell Carcinoma Metastatic; Synchronous Neoplasm	Procedure: Cytoreductive nephrectomy; Other: Tissue sampling	Not Applicable

Detailed Description:

OUTLINE: This is a multicenter trial, patients are stratified according to institution, treatment choice, number of IMDC risk factors, and combined elevated neutrophil-lymphocyte ratio and hyponatremia.

All patients will receive induction checkpoint immunotherapy immediately after inclusion. After 3 months or a total of 4 series of nivolumab combined with ipilimumab or a TKI/IO-combination, the patient will be discussed for resectability at the multidisciplinary meeting (MDT). Whether the patient is eligible for cytoreductive nephrectomy is at the discretion of the urologist at the local MDT. Patients with ≤ 3 IMDC risk factors and deemed suitable for cytoreductive nephrectomy will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 3 month evaluation continue systemic therapy for 3 months, followed by a 2nd evaluation. Patients with ≤ 3 IMDC risk factors and deemed suitable for cytoreductive nephrectomy at 2nd evaluation will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 6 month evaluation continue systemic therapy. Nivolumab may continue until unacceptable toxicity or total treatment length of 2 years from inclusion.

ARM A: Deferred cytoreductive nephrectomy, followed by maintenance nivolumab or a TKI/IO-combination.

ARM B: No surgery, receive maintenance nivolumab or a TKI/IO-combination.

Patients undergo tumor tissue, blood, and stool collection at baseline, 3 and 6 months, for planned translational research.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Randomized Trial of Deferred Cytoreductive Nephrectomy in Synchronous Metastatic Renal Cell Carcinoma Receiving Checkpoint Inhibitors: a DaRenCa and NoRenCa Trial Evaluating the Impact of Surgery or No Surgery. The NORDIC-SUN-Trial
• Actual Study Start Date: July 6, 2020
• Estimated Primary Completion Date: September 1, 2026
• Estimated Study Completion Date: September 1, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Deferred nephrectomy; Surgery after induction therapy with IO/IO or a TKI/IO-combination, followed by maintenance therapy with nivolumab or a TKI/IO-combination.	Procedure: Cytoreductive nephrectomy; Partial or complete nephrectomy by open, laparoscopic, or robotic approach.; Other: Tissue sampling; Tumor biopsies, blood, and stool specimens for translational biomarker research will be sampled at baseline and after 3 or 6 months.
Active Comparator: No surgery; Induction therapy wih IO/IO or a TKI/IO-combination, followed by maintenance therapy with nivolumab or a TKI/IO-combination.	Other: Tissue sampling; Tumor biopsies, blood, and stool specimens for translational biomarker research will be sampled at baseline and after 3 or 6 months.

Outcome Measures

Primary Outcome Measures :

1. Overall survival [ Time Frame: Minimum 3 years follow-up ]
   Calculated from the date of inclusion, to the date of death of any cause or censored at the date at last follow-up.

Secondary Outcome Measures :

1. Progression free survival [ Time Frame: 3 years follow-up ]
   According to the RECIST v1.1
2. Time to subsequent systemic therapy [ Time Frame: 3 years follow-up ]
   Calculated from date of inclusion to date of initiation of subsequent therapy or death of any cause or censored at the date of last follow-up
3. Objective response rate [ Time Frame: 3 years follow-up ]
   According to the RECIST v1.1
4. Rate of patients meeting randomization criteria [ Time Frame: 3 or 6 months ]
   Compared with baseline values
5. Fractional percentage of tumor volume (ratio of primary tumor measurement to total sum of target lesions) to survival outcome in deferred cytoreductive nephrectomy patients and no surgery patients [ Time Frame: 3 years follow-up ]
6. Number of participants with treatment-related adverse events as by Common Terminology Criteria for Adverse Events version 5.0. [ Time Frame: 3 years follow-up ]
7. Number of participant with surgical morbidity assessed according to the Clavien-Dindo classification of surgical complications [ Time Frame: 3 years follow-up ]
8. Tumor infiltrating lymphocytes baseline and after surgery compared with OS, PFS, TST, ORR [ Time Frame: 3 year follow-up ]
   As part of a biomarker analysis
9. Immune subsets in blood measured by flowcytometry in serial samples compared with OS, PFS, TST, ORR. [ Time Frame: 3 year follow-up ]
   As part of a biomarker analysis
10. Genetic profile of circulation tumor DNA measured by Next generation sequencing (NGS), compared with OS, PFS, TST, ORR. [ Time Frame: 3 year follow-up ]
    As part of a biomarker analysis
11. Genetic profile of primary tumor tissue measured by measured by NGS compared with OS, PFS, TST, ORR. [ Time Frame: 3 year follow-up ]
    As part of a biomarker analysis
12. Profile of gut microbiome measured by NGS compared OS, PFS, TST, ORR. [ Time Frame: 3 year follow-up ]
    As part of a biomarker analysis

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Signed written informed consent obtained prior to any study specific procedures.
2. Patient must be willing and able to comply with the protocol.
3. Age ≥18.
4. Core needle biopsy proven metastatic renal cell carcinoma - all histologic subtypes acceptable.
5. Synchronous metastatic renal cell carcinoma with the primary tumor present in the kidney.
6. Measurable disease as per RECIST v 1.1
7. Patients for which Nivolumab/Ipilimumab or a TKI/IO-combination is considered indicated according to the recommendations by the European Medicines Agency and the national health authorities of participating countries. The prescription of nivolumab/ipilimumab or a TKI/IO-combination in the circumstances of the study is considered as a standard treatment.
8. Females with a negative serum pregnancy test unless childbearing potential can be otherwise excluded (postmenopausal, hysterectomy or oophorectomy) and not lactating.
9. 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).
10. Karnofsky Performance status ≥70
11. Life expectancy of greater than 4 months.

12. The required laboratory values are as follows:

    • Adequate bone marrow function (Leucocytes > 3.0 x 109/l, platelets > 100 x 109/l, hemoglobin > 6.0 mmol/l or > 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 or ≤ 5 x ULN if liver lesions)
    • Adequate kidney function (eGFR > 35 mL/min)

Exclusion Criteria:

1. Prior systemic treatment for mRCC
2. Other cancer within 3 years (except in situ basal cell carcinoma and localised prostate cancer with undetectable PSA).
3. Major surgical procedure, open surgical biopsy, or significant traumatic injury within 28 days prior to enrollment
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. Known hypersensitivity to monoclonal antibodies.
9. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
10. Any positive test for hepatitis B- or C-Virus indicating acute or chronic infection.
11. Oral or i.v. antibiotics administered 14 days prior to initiation of systemic therapy.

Contacts and Locations

Contacts

Contact: Niels Fristrup, MD PhD; 004520914161; niels.fristrup@rm.dk

Locations

Denmark

Department of Oncology, Aarhus University Hospital; Recruiting

Aarhus, Central Region Of Denmark, Denmark, 8200

Contact: Niels Fristrup, MD PhD 004520914161 niels.fristrup@rm.dk

Department of Oncology, Herlev Hospital; Not yet recruiting

Herlev, Denmark, 2730

Contact: Anne Kirstine Moeller, MD, PhD

Department of Oncology, Odense University Hospital; Not yet recruiting

Odense, Denmark, 5000

Contact: Niels Viggo Jensen, MD +45 6611 3333 Niels.Viggo.Jensen@rsyd.dk

Sponsors and Collaborators

Niels Fristrup

Aarhus University Hospital

Investigators

• Principal Investigator: Niels Fristrup, MD PhD; Department of Oncology, Aarhus University Hospital.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kuusk T, Abu-Ghanem Y, Mumtaz F, Powles T, Bex A. Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy. Curr Opin Urol. 2021 May 1;31(3):262-269. doi: 10.1097/MOU.0000000000000868.

• Responsible Party: Niels Fristrup, MD PhD, Aarhus University Hospital
• ClinicalTrials.gov Identifier: NCT03977571
• Other Study ID Numbers: NORDIC-SUN
• First Posted: June 6, 2019
• Last Update Posted: June 16, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Niels Fristrup, Aarhus University Hospital:

Cytoreduction Surgical Procedures; Nephrectomy; Ipilimumab; Nivolumab; Laboratory biomarker analysis; Gene Expression; Liquid Biopsy

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Neoplasms, Multiple Primary; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases