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

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ClinicalTrials.gov Identifier: NCT05119010
Recruitment Status : Not yet recruiting
First Posted : November 12, 2021
Last Update Posted : November 12, 2021
Sponsor:
Information provided by (Responsible Party):
Gustave Roussy, Cancer Campus, Grand Paris

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Renal Cell Carcinoma Dietary Supplement: Continuous ketogenic diet Dietary Supplement: Discontinuous ketogenic diet Dietary Supplement: beta-hydroxybutyrate (BHB) supplementation Not Applicable

Detailed Description:

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 sequentially enrolled in a 1:1:1:1 ratio 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: A Pilot Study Evaluating a Ketogenic Diet Concomitant to Nivolumab and Ipilimumab in Patients With Metastatic Renal Cell Carcinoma
Estimated Study Start Date : November 8, 2021
Estimated Primary Completion Date : November 8, 2024
Estimated Study Completion Date : November 8, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: A
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
ARM A : continuous ketogenic diet
Experimental: B
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
ARM B : discontinuous ketogenic diet
Experimental: C
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
ARM C : BHB supplementation
No Intervention: D
patients will receive standard diet (without any diet restrictions) and be followed up as in arms A, B, C.


Outcome Measures
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Primary Outcome Measures :
  1. Objective response rate [ Time Frame: at 8 weeks after diet initiation. ]
    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.


Secondary Outcome Measures :
  1. Safety of Nivolumab plus Ipilimumab concomitant to a special diet [ Time Frame: 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. ]
    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.

  2. Assessment of weight [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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.

  3. Assessment of albuminemia [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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.

  4. Assessment of prealbuminemia [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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.

  5. Assessment of C reactive protein [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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.

  6. Assessment of sarcopenia [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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).

  7. Assessment of Quality of Life (QoL) [ Time Frame: At screening and 9 weeks after diet initiation ]
    explore the evolution of Patient Reported Outcomes using EORTC QLQ 30 file in all treated patients.

  8. progression-free survival assessment [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    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.

  9. Sarcopenic event-free survival (SFS) [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    SFS will be estimated from intervention starting.

  10. Overall survival (OS) [ Time Frame: from the first day of diet and up to 2 years from diet initiation ]
    OS is specified as the time between the date of the starting of the diet and the date of the death whatever the cause.


Eligibility Criteria
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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05119010


Contacts
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Contact: Elodie LECERF, MSc +33142114211 (26 17) elodie.lecerf@gustaveroussy.fr
Contact: Thibaud MOTREFF, MSc +33142116643 thibaud.motreff@gustaveroussy.fr

Sponsors and Collaborators
Gustave Roussy, Cancer Campus, Grand Paris
Investigators
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Principal Investigator: Emeline COLOMBA BLAMEBLE, MD Gustave Roussy, Cancer Campus, Grand Paris
More Information
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Publications:
Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019 Oct;20(10):1370-1385. doi: 10.1016/S1470-2045(19)30413-9. Epub 2019 Aug 16. Erratum in: Lancet Oncol. 2019 Aug 21;:. Erratum in: Lancet Oncol. 2020 Jun;21(6):e304. Lancet Oncol. 2020 Nov;21(11):e518.
Zhou Z, Hagopian K, Roberts M, et al. A Ketogenic Diet Increases Markers of Mitochondrial Content in a Tissue Specific Manner in Adult Mice. FASEB J. 2017;31(1_supplement):lb482-lb482. doi:10.1096/fasebj.31.1_supplement.lb482
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2.
Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J; MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M'rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P. Enterotypes of the human gut microbiome. Nature. 2011 May 12;473(7346):174-80. doi: 10.1038/nature09944. Epub 2011 Apr 20. Erratum in: Nature. 2011 Jun 30;474(7353):666. Nature. 2014 Feb 27;506(7489):516.

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Responsible Party: Gustave Roussy, Cancer Campus, Grand Paris
ClinicalTrials.gov Identifier: NCT05119010    
Other Study ID Numbers: 2020/3206
First Posted: November 12, 2021    Key Record Dates
Last Update Posted: November 12, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
 Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases