Neoadjuvant Study With Combination Immuno-oncology for Primary Clear Cell Renal Cell Cancer

NCT05148546 | Active Not Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: M21NSCCA209-6DJ2021-002360-51
• Study Type: interventional
• Target: 69
• Locations: 2 countries
• Sites: 2

Brief Summary

The NESCIO-trial is a multicenter, randomized, open-label, three-arm phase II trial investigating different combinations of neoadjuvant immunotherapy in patients with primary, resectable, intermediate to high-risk, clear-cell renal cell carcinoma. In this trial patients will be randomized 1:1:1 to receive either 2 cycles of nivolumab 360mg every 3 weeks (arm A), 2 cycles of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks (arm B) or 2 cycles of relatlimab 360mg + nivolumab 360mg every 3 weeks (arm C), prior to surgery at week 7. After 42 patients (14 per arm) have been recruited, an interim analysis will be performed to evaluate the observed efficacy and toxicity within each arm and either allow for early discontinuation of the treatment or continuing recruitment for the second stage. As the primary endpoint, the pathological response (decrease in tumor) will be evaluated. If at most one pathologic response in the primary tumor is observed, the treatment arm will be closed for insufficient activity on the primary tumor. If at least 2 pathologic responses are observed, 9 additional patients will be included to a total of 23 patients per cohort. A maximum of 69 patients will be recruited for this study. Follow up will start at week 12 with a CT-scan according to the national/center's standard. Patients will be evaluated every 3 months by physical examination and lab testing for up to two years, thereafter according to institutional guidelines up to 5 years following surgery.

Conditions

Renal Cell Carcinoma

Keywords

Resectable renal cell carcinoma; Checkpoint inhibition; Immunotherapy; PD-1 inhibitor; CTLA-4 inhibitor; LAG-3 inhibitor; Nivolumab; Ipilimumab; Relatlimab; Neoadjuvant; NESCIO; M21NSC; Checkpoint blockade

Outcome Measures

Primary Outcomes (1)

• Pathologic response rate

  Pathologic response rate is defined as the proportion of patients demonstrating a complete pathologic or partial pathologic response, according to central revision (pathology of NKI)

  At 6 weeks

Secondary Outcomes (10)

• Safety, measured by the frequency of immune-related adverse events leading to postponing of surgery for >2 weeks

  At 8 weeks

• Objective response rate

  At 6 weeks

• Recurrence Free Survival (RFS)

  Up to 5 years after start of treatment

• Event-free Survival (EFS)

  Up to 5 years after start of treatment

• Rate of distant metastases

  Up to 5 years after start of treatment

Study Arms (3)

A: Neoadjuvant nivolumab

EXPERIMENTAL

Neoadjuvant 2 cycles of nivolumab 360mg every 3 weeks

Drug: Neoadjuvant nivolumab

B: Neoadjuvant nivolumab + ipilimumab

EXPERIMENTAL

Neoadjuvant 2 cycles of nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks

Drug: Neoadjuvant nivolumab; Drug: Neoadjuvant ipilimumab

C: Neoadjuvant nivolumab + relatlimab

EXPERIMENTAL

Neoadjuvant 2 cycles of nivolumab 360mg + relatlimab 360mg every 3 weeks

Drug: Neoadjuvant nivolumab; Drug: Neoadjuvant relatlimab

Interventions

Neoadjuvant nivolumab DRUG

Patients will receive 2 cycles of nivolumab 360mg (arm A and C) or 3mg/kg (arm B) every 3 weeks followed by a nephrectomy.

Also known as: Opdivo

A: Neoadjuvant nivolumab; B: Neoadjuvant nivolumab + ipilimumab; C: Neoadjuvant nivolumab + relatlimab

Neoadjuvant ipilimumab DRUG

Patients will receive 2 cycles of ipilimumab 1mg/kg every 3 weeks followed by a nephrectomy.

Also known as: Yervoy

B: Neoadjuvant nivolumab + ipilimumab

Neoadjuvant relatlimab DRUG

Patients will receive 2 cycles of relatlimab 360mg every 3 weeks followed by a nephrectomy.

C: Neoadjuvant nivolumab + relatlimab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults at least 18 years of age;
• World Health Organization (WHO) Performance Status 0 or 1;
• Histologically confirmed resectable clear cell RCC (measurable according to RECIST 1.1), that can be biopsied, and no history of distant metastases;
• Intermediate to high risk will be based on clinical TNM and biopsy nuclear grade. These are:
• cT1b-cT2a grade 4 cN0 cM0
• cT2b grade 3 cN0 cM0
• cT3 any grade cN0 cM0
• cT4 any grade cN0 cM0
• cT any cN1 (fully resectable) cM0
• No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years;
• Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse;
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1, or LAG-3;
• No immunosuppressive medications within 2 weeks prior start immunotherapy;
• Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN, normal CK and Troponin T, normal LDH;
• Women of childbearing potential must use appropriate method(s) of contraception. They should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug;

You may not qualify if:

• Distantly metastasized RCC;
• Brain metastases (based on symptoms);
• Non-clear cell RCC;
• No measurable lesion according to RECIST 1.1;
• Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy;
• Prior CTLA-4 or PD-1/PD-L1 or LAG-3 targeting immunotherapy;
• Radiotherapy prior or post-surgery;
• Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate;
• Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
• Allergies and Adverse Drug Reactions (like mastocytosis);
• History of severe hypersensitivity reaction to any monoclonal antibody;
• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug(s) hazardous or obscure the interpretation of toxicity or adverse events;
• Pregnant or nursing;
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
• Participants with history of myocarditis, regardless of etiology;

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (2)

Netherlands Cancer Institute

Amsterdam, North Holland, 1066CX, Netherlands

Location

Royal Free London NHS Foundation Trust

London, NW3 2QG, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; 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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• John Haanen, Prof

  Medical oncologist/researcher

  PRINCIPAL INVESTIGATOR

• Axel Bex, Prof

  Urologist/researcher

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open-label three-arm randomized phase II trial

Study Record Dates

• First Submitted: November 25, 2021
• First Posted: December 8, 2021
• Study Start: April 28, 2022
• Primary Completion: April 22, 2025
• Study Completion (Estimated): April 1, 2029
• Last Updated: September 30, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); GB (1)