Evaluation study of a treatement with Nivolumab and Ipilimumab or tKi according to molecular group in naïve metastatic Kidney cancer

Prior treatment

• Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant edema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
• History of DVT unless adequately treated with low molecular weight heparin
• History of pulmonary embolism within the past 6m unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks
• Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
• Prior systemic treatment with VEGF or VEGF receptor-targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) except in an adjuvant setting with a free interval of more than 1 year.
• Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug
• Focal radiation therapy less than 14 days prior to the first dose of study drug.
• Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
• Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of SD. Inhaled steroids and adrenal replacement steroid doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

Other illness

• History of cerebrovascular accident including transient ischemic attack within the past 12 months.
• Known history of COPD
• Known history of uveitis or complaint of double vision
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
• Serious, non-healing wound or ulcer
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
• Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the Investigator’s opinion, would increase the risk associated with study participation or study drug administration, or interfere with the interpretation of safety results
• Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of TKI (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
• Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type 1 diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
• Uncontrolled adrenal insufficiency
• Poorly controlled hypertension (defined as SBP of >150 mmHg or DBP of >90 mmHg), despite antihypertensive therapy
• History of any of the following CV conditions within 12m of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the NYHA.

Lab values

• Any of the following laboratory test findings: a) WBC <2,000/mm3 b) Hemoglobin ≤9.0 g/dL c) Neutrophils <1,500/mm3 d) Platelets <100,000/mm3 e) AST or ALT >3 x ULN (>5 x ULN if liver metastases are present) f) Lipase and amylase > 1.5 ULN g) Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL) h) Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or calculated by Cockroft-Gault formula) i) Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if > 1.0 g of protein patient will not be included.
• Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as >450 msec for males and >470 msec for females, where QTcF = QT / 3√RR.

Other

• Any requirement for anti-coagulation, except for low molecular weight heparin

• Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
• Metastatic (American Joint Committee on Cancer [AJCC] Stage IV) RCC
• No prior systemic therapy for mRCC (patients with relapse >1 year after adjuvant treatment discontinuation are eligible)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Frozen tumor samples or fresh tumor samples immediately stored in "RNA later" medium (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration [FNA] and bone metastases samples are not acceptable for submission).
• Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis
• Molecular group has to be determined prior to randomization.