A Pilot Study Evaluating a Ketogenic Diet Concomitant to Nivolumab and Ipilimumab in Patients With Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Pilot Study Evaluating a Ketogenic Diet Concomitant to Nivolumab and Ipilimumab in Patients With Metastatic Renal Cell Carcinoma

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Dietary Supplement: Continuous ketogenic diet
* Dietary Supplement: Discontinuous ketogenic diet
* Dietary Supplement: beta-hydroxybutyrate (BHB) supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women ≥ 18 years Patients with a histologically confirmed Renal Cell Carcinoma with a clear-cell component, sarcomatoid or rhabdoid 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 Patients who have not received a prior systemic therapy. Prior cytokine therapies (e.g. interleukine-2, interferon-α), vaccine therapy are allowed. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Intermediate or poor risk group patients measured by the IMDC model 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 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. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed Patient should be able and willing to comply with study visits and procedures as per protocol Patients must be affiliated to a social security system or beneficiary of the same 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 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: Weight loss > 5% in the last month Weight loss > 10% during last 6 months Albumin <30 g/l 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. Fatty acid oxidation disturbances 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. 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. Failure to submit to study clinical and biological follow-up for medical, geographic or social reasons Pregnant or breastfeeding women Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent Known drug or alcohol abuse 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) Has a known history of active tuberculosis (Mycobacterium tuberculosis) 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. 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. Has evidence of interstitial lung disease or active, non-infectious pneumonitis Has an active infection requiring systemic therapy 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) Positive for Human Immunodeficiency Virus (HIV) antibody testing 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be included sequentially in each arm from arm A to arm D. When the first inclusion arm A will be full with 15 patients who passed the screening, then next patients will be enrolled in arm B, then it will be the same process with arm C and last patients will be included in arm D.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>patients will be asked to follow in a continuous way a very low-carbohydrate, high-fat diets, which strictly limit carbohydrate consumption (less than 40g / day) and allow unlimited consumption of high-fat foods, such as pork belly, butter, coconuts oils, fat meat, eggs and cheese, etc… (cf appendix A). Patients will be provided with 2 meals (lunch and dinner), every meal with 2 dishes (first course and main course) and bread for every day for 3 months (ELIOR partnership). | Dietary Supplement: Continuous ketogenic diet<br>* ARM A : continuous ketogenic diet<br>|
| Experimental: B<br>patients will be asked to follow in a discontinuous way (15 days on, 15 days off) a very low-carbohydrate, high-fat diets, which strictly limit carbohydrate consumption (less than 40g / day) and allow unlimited consumption of high-fat foods, such as pork belly, butter, coconuts oils, fat meat, eggs and cheese…etc (cf appendix A). Patients will be provided with 2 meals (lunch and dinner), every meal with 2 dishes (first course and main course) and bread for every day for the ketogenic diet period for 3 months (ELIOR partnership). | Dietary Supplement: Discontinuous ketogenic diet<br>* ARM B : discontinuous ketogenic diet<br>|
| Experimental: C<br>patients will receive oral liquid ketone supplement BHB monoester, 2 tablespoons three times per day (depending on patient weight: at least 1g/kg weight body/day) 15 days-on 15 days off during 3 months. We would recommend taking it at least 30 to 60 min before meal times and they will receive standard diet (without any diet restrictions). | Dietary Supplement: beta-hydroxybutyrate (BHB) supplementation<br>* ARM C : BHB supplementation<br>|
| No Intervention: D<br>patients will receive standard diet (without any diet restrictions) and be followed up as in arms A, B, C. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Preliminary activity will be assessed by measuring objective response rate (ORR) (partial/complete response) of Nivolumab plus Ipilimumab concomitant to a special diet (KD continuous or discontinuous) or standard diet (SD) with or without (BHB) according to RECIST v1.1 at 8 weeks. | at 8 weeks after diet initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Nivolumab plus Ipilimumab concomitant to a special diet | the safety of Nivolumab plus Ipilimumab concomitant to a special diet (ketogenic diet, continuous or discontinuous) or standard diet (SD) with or without BHB will be measured by the rate of all and grade 3-4 adverse events (AEs) according to CTCAEv4, and compare the rate to historical datas. | Events reported from the first day of diet and up to and including 100 days following the last day of diet could be included in estimating this incidence rate. | 
| Assessment of weight | Assessment of weight in kilograms by baseline test and follow up in order to evaluate the impact of the diet concomitant to immunotherapy on nutritional status, muscle mass, and sarcopenia. | from the first day of diet and up to 2 years from diet initiation | 
| Assessment of albuminemia | Assessment of albuminemia in g/L in order to evaluate the impact of the diet concomitant to immunotherapy on nutritional status, muscle mass, and sarcopenia. | from the first day of diet and up to 2 years from diet initiation | 
| Assessment of prealbuminemia | Assessment of prealbuminemia in g/L in order to evaluate the impact of the diet concomitant to immunotherapy on nutritional status, muscle mass, and sarcopenia. | from the first day of diet and up to 2 years from diet initiation | 
| Assessment of C reactive protein | Assessment of C reactive protein in mg/L in order to evaluate the impact of the diet concomitant to immunotherapy on nutritional status, muscle mass, and sarcopenia. | from the first day of diet and up to 2 years from diet initiation | 
| Assessment of sarcopenia | Sarcopenia will be assessed according to SliceOmatic software V5.0 and preestablished thresholds of skeletal muscle tissue (-29 to +150 Hounsfield units). Axial L3 sections will be used to measure the total muscle area (TMA) and calculate skeletal muscle index (SMI, cm²/m²). Sarcopenia is defined as SMI lower than a sex-based threshold (<55.4 in men and <38.9 in women). | from the first day of diet and up to 2 years from diet initiation | 
| Assessment of Quality of Life (QoL) | explore the evolution of Patient Reported Outcomes using EORTC QLQ 30 file in all treated patients. | At screening and 9 weeks after diet initiation | 
| progression-free survival assessment | PFS is specified as the time between the date of the starting of the diet and the first date of documented progression, based on assessments (as per RECIST v1.1 criteria), or death due to any cause. | from the first day of diet and up to 2 years from diet initiation | 
| Sarcopenic event-free survival (SFS) | SFS will be estimated from intervention starting. | from the first day of diet and up to 2 years from diet initiation | 
| Overall survival (OS) | OS is specified as the time between the date of the starting of the diet and the date of the death whatever the cause. | from the first day of diet and up to 2 years from diet initiation |