Recruitment challenges: competition with another microbiome trial, patient refusal to join a dietary intervention study, poor tolerance of oral DPD (Grade 2 mucositis), and issues with organizing biological sample collection.

The purpose of this study is to assess objective response rate (partial and complete response) of Nivolumab and Ipilimumab concomitant to a special diet (ketogenic diet, continuous or discontinuous) or standard diet with or without BHB according to RECIST v1.1 at 8 weeks.

After being informed about the study and potential risks, all patients giving informed consent will undergo a 10 days screening period to determine eligibility for study entry. At week1day1, patients who meet the eligibility requirements will be enrolled in to :

• Arm A : continuous ketogenic diet for 3 months
• Arm B : discontinuous ketogenic diet (15 days on, 15 days off) for 3 months
• Arm C : oral liquid ketone supplement BHB monoester, 15 days-on 15 days off during 3 months.
• Arm D : standard diet (without any diet restrictions). and follow up as in arms A, B, C.

All patients will receive Nivolumab plus Ipilimumab according to practical routine.

Inclusion Criteria:

1. Adult men and women ≥ 18 years
2. Patients with a histologically confirmed Renal Cell Carcinoma with a clear-cell component, sarcomatoid or rhabdoid
3. Patients with metastatic (AJCC stage IV) Renal Cell Carcinoma, with at least one measurable lesion by CT Scan or MRI according to RECIST 1.1 or with clinically apparent disease that can be reliably monitored by the investigator
4. Patients who have not received a prior systemic therapy. Prior cytokine therapies (e.g. interleukine-2, interferon-α), vaccine therapy are allowed.
5. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
6. Intermediate or poor risk group patients measured by the IMDC model
7. Patients with brain metastases will be eligible if they are: asymptomatic, without edema, not on corticosteroids more than 10 mg per day or already treated
8. Patients treated with radiation therapy will be eligible if they are: palliative, on focal radiation therapy, on immunosuppressive doses of systemic corticosteroids less than 10 mg per day.
9. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed
10. Patient should be able and willing to comply with study visits and procedures as per protocol
11. Patients must be affiliated to a social security system or beneficiary of the same
12. Women of childbearing potential must have a negative serum pregnancy test done within 24 hours prior to diet initiation. Potentially reproductive patients must agree to use an effective contraceptive method or practice adequate methods of birth control or practice complete abstinence while on treatment with Nivolumab and Ipilimumab
13. Women who are breastfeeding should discontinue nursing prior to the first dose of study drug and until 6 months after the last dose

Exclusion Criteria:

1. Weight loss > 5% in the last month

2. Weight loss > 10% during last 6 months

3. Albumin <30 g/l

4. Known or underlying medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or adverse events.

5. Fatty acid oxidation disturbances

6. Uncontrolled diabetes defined as a hemoglobin A1C level > 8%. Diabetes is not exclusionary provided the patient is not maintained with either oral medications or insulin.

7. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements as determined by study team members.

8. Failure to submit to study clinical and biological follow-up for medical, geographic or social reasons

9. Pregnant or breastfeeding women

10. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent

11. Known drug or alcohol abuse

12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment (except local/topical or aerosol steroids)

13. Has a known history of active tuberculosis (Mycobacterium tuberculosis)

14. Has had a prior monoclonal antibody within 4 weeks or 5 half-life time (whichever is shorter) prior to the first dose of study treatment or who has not recovered (i.e., ≥ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

15. Has an active autoimmune / immune mediated inflammatory disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjörgen's syndrome will not be excluded from the study.

16. Has evidence of interstitial lung disease or active, non-infectious pneumonitis

17. Has an active infection requiring systemic therapy

18. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

19. Positive for Human Immunodeficiency Virus (HIV) antibody testing

20. Active or chronic hepatitis C and/or B infection. Patients with past/resolved HBV infection (defined as the presence of anti-hepatitis B core antibody, IgG anti-HBs +) are eligible. Hepatitis B virus DNA should be obtained in these patients prior to the first dose of study treatment. Patients positive for hepatitis C virus antibody are eligible only if PCR is negative for HCV RNA

21. Patients with altered hematopoietic or organ function, as indicated by the following criteria (assessed within 5 days prior registration):

    • White blood cell < 3000/μL
    • Polynuclear neutrophils < 1.5 x 109/L
    • Platelets < 100 x 109/L
    • Hemoglobin < 7.0 g/mL
    • Alanine aminotransferase/aspartate aminotransferase > 3.0 x ULN in the absence of liver metastases or > 5x upper limit of normal in the presence of liver metastases
    • Bilirubin > 1.5 x ULN (except Gilbert Syndrome: < 3.0 mg/dL)
    • Creatinine clearance ≤ 35 mL/min (measured or calculated by Cockcroft and Gault formula)