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

Inclusion Criteria:

• 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:

1. cT1b-cT2a grade 4 cN0 cM0
2. cT2b grade 3 cN0 cM0
3. cT3 any grade cN0 cM0
4. cT4 any grade cN0 cM0
5. cT any cN1 (fully resectable) cM0

• No other malignancies, except adequately treated and a cancer-related life-expectancyof more than 5 years;
• Patient willing to undergo triple tumor biopsies and extra blood withdrawal duringscreening 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 andTroponin T, normal LDH;
• Women of childbearing potential must use appropriate method(s) of contraception. Theyshould use an adequate method to avoid pregnancy for 23 weeks (30 days plus the timerequired for nivolumab to undergo five half-lives) after the last dose ofinvestigational drug;
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to thestart of study treatment;
• Women who are not of childbearing potential (i.e., who are postmenopausal), orsurgically sterile as well as azoospermic men do not require contraception;
• Patient is capable of understanding and complying with the protocol requirements andhas signed the Informed Consent document.

Exclusion Criteria:

• 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 autoimmunedisease, or history of syndrome that required systemic steroids or immunosuppressivemedications, 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 orchronic infection; if treated and being at least one year free from HCV patients areallowed to participate;
• Patients will be excluded if they have known history of testing positive for humanimmunodeficiency 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 theadministration of study drug(s) hazardous or obscure the interpretation of toxicity oradverse events;
• Pregnant or nursing;
• Concurrent medical condition requiring the use of immunosuppressive medications, orimmunosuppressive doses of systemic or absorbable topical corticosteroids;
• Use of other investigational drugs before study drug administration 30 days and 5half-times before study inclusion. Relatlimab-specific exclusion Criteria:
• Participants with history of myocarditis, regardless of etiology;
• Troponin T (TnT) > 2 × institutional ULN. Participants with TnT levels between > 1 to 2 × ULN will be permitted if a repeat levels within 24 hours are ≤ 1 ULN. If TnTlevels are between >1 to 2 × ULN within 24 hours, the participant may undergo acardiac consultation and be considered for treatment, following cardiologistrecommendation. When repeat levels within 24 hours are not available, a repeat testshould be conducted as soon as possible. If TnT repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac consultation and be considered fortreatment, following cardiologist recommendation. Notification of the decision toenroll the participant following cardiologist recommendation has to be made to the BMSMedical Monitor or designee.
• Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% byeither transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan (TTEpreferred test) within 6 months prior to start of study treatment.