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Metastatic Renal Cell CarcinomaKETOREINNCT05119010

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

A study testing Continuous ketogenic diet, Discontinuous ketogenic diet and beta-hydroxybutyrate (BHB) supplementation in people with Metastatic Renal Cell Carcinoma, run by Gustave Roussy, Cancer Campus, Grand Paris at 3 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Renal Cell Carcinoma
What is being tested?
Continuous ketogenic diet, Discontinuous ketogenic diet and beta-hydroxybutyrate (BHB) supplementation
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
3 sitesFrance
Study dates
24 Mar 2023to 22 May 2024
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 13Show fewer
  • 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

Who cannot join

  • 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.
Show all 28Show fewer
  • 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)

Trial locations and contacts

3 sites in 1 country.

France3 sites

  • Hôpital Européen Georges Pompidou

    Paris, 75015

  • Hôpitaux Cochin-Port-Royal

    Paris, 75679

  • Gustave Roussy

    Villejuif, Val-de-Marne, 94805

Other trials in France

About this study

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.

Read the 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 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.

Being tested
Continuous ketogenic diet, Discontinuous ketogenic diet, beta-hydroxybutyrate (BHB) supplementation
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Continuous ketogenic dietDietary supplement

    ARM A : continuous ketogenic diet

  • Discontinuous ketogenic dietDietary supplement

    ARM B : discontinuous ketogenic diet

  • beta-hydroxybutyrate (BHB) supplementationDietary supplement

    ARM C : BHB supplementation

Study groups in NCT05119010
Study groupRoleWhat they receive
AExperimentalpatients 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).
Receives: Dietary Supplement: Continuous ketogenic diet
BExperimentalpatients 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).
Receives: Dietary Supplement: Discontinuous ketogenic diet
CExperimentalpatients 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).
Receives: Dietary Supplement: beta-hydroxybutyrate (BHB) supplementation
DNo interventionpatients will receive standard diet (without any diet restrictions) and be followed up as in arms A, B, C.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: at 8 weeks after diet initiation.

Secondary outcomes (10)

  1. 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 data.

    Measured: 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.

  2. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

  3. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

  4. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

  5. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

  6. 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).

    Measured: from the first day of diet and up to 2 years from diet initiation

  7. Assessment of Quality of Life (QoL)

    explore the evolution of Patient Reported Outcomes using EORTC QLQ 30 file in all treated patients.

    Measured: At screening and 9 weeks after diet initiation

  8. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

  9. Sarcopenic event-free survival (SFS)

    SFS will be estimated from intervention starting.

    Measured: from the first day of diet and up to 2 years from diet initiation

  10. 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.

    Measured: from the first day of diet and up to 2 years from diet initiation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Nov 2021
  2. Study start24 Mar 2023
  3. Primary completion22 May 2024
  4. Study completion22 May 2024

Why it stopped: 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.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
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. However, the clinician has the option of including the patient in the standard diet arms with or without BHB (arm C or D), instead of the ketogenic diet arms (arm A or B), if the patient's organizational constraints do not allow for a strict ketogenic diet.
Masking
None (open label)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05119010
Sponsor's protocol ID
2020-A03550-39
Other IDs
2020/3206
Acronym
KETOREIN
Status last verified
Dec 2024
First submitted
21 Oct 2021
Last updated
5 Dec 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Dashti HM, Mathew TC, Hussein T, Asfar SK, Behbahani A, Khoursheed MA, Al-Sayer HM, Bo-Abbas YY, Al-Zaid NS. Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol. 2004 Fall;9(3):200-5.

    PubMed 19641727

  • Woolf EC, Scheck AC. The ketogenic diet for the treatment of malignant glioma. J Lipid Res. 2015 Jan;56(1):5-10. doi: 10.1194/jlr.R046797. Epub 2014 Feb 6.

    PubMed 24503133

  • Chung HY, Park YK. Rationale, Feasibility and Acceptability of Ketogenic Diet for Cancer Treatment. J Cancer Prev. 2017 Sep;22(3):127-134. doi: 10.15430/JCP.2017.22.3.127. Epub 2017 Sep 30.

    PubMed 29018777

  • Levesque S, Pol JG, Ferrere G, Galluzzi L, Zitvogel L, Kroemer G. Trial watch: dietary interventions for cancer therapy. Oncoimmunology. 2019 Apr 3;8(7):1591878. doi: 10.1080/2162402X.2019.1591878. eCollection 2019.

    PubMed 31143510

  • Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daillere R, Thelemaque C, Grajeda-Iglesias C, Alves Costa Silva C, Aprahamian F, Lefevre D, Zhao L, Ryffel B, Colomba E, Arnedos M, Drubay D, Rauber C, Raoult D, Asnicar F, Spector T, Segata N, Derosa L, Kroemer G, Zitvogel L. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight. 2021 Jan 25;6(2):e145207. doi: 10.1172/jci.insight.145207.

    PubMed 33320838

  • Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.

    PubMed 29562145

  • Motzer RJ, Rini BI, McDermott DF, Aren Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthelemy 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, Grunwald 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.

    PubMed 31427204

  • Gianchecchi E, Fierabracci A. Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression. Front Immunol. 2018 Oct 17;9:2374. doi: 10.3389/fimmu.2018.02374. eCollection 2018.

    PubMed 30386337

  • Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009 May;229(1):114-25. doi: 10.1111/j.1600-065X.2009.00767.x.

    PubMed 19426218

  • Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004 Jul 15;173(2):945-54. doi: 10.4049/jimmunol.173.2.945.

    PubMed 15240681

  • Lazar-Molnar E, Scandiuzzi L, Basu I, Quinn T, Sylvestre E, Palmieri E, Ramagopal UA, Nathenson SG, Guha C, Almo SC. Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy. EBioMedicine. 2017 Mar;17:30-44. doi: 10.1016/j.ebiom.2017.02.004. Epub 2017 Feb 6.

    PubMed 28233730

  • Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest. 2013 Sep;123(9):3685-92. doi: 10.1172/JCI69741. Epub 2013 Sep 3.

    PubMed 23999443

  • Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol. 2014;2:963-70. doi: 10.1016/j.redox.2014.08.002. Epub 2014 Aug 7.

    PubMed 25460731

  • Aykin-Burns N, Ahmad IM, Zhu Y, Oberley LW, Spitz DR. Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J. 2009 Feb 15;418(1):29-37. doi: 10.1042/BJ20081258.

    PubMed 18937644

  • 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

Questions about this trial

What is this clinical trial studying?

A study testing Continuous ketogenic diet, Discontinuous ketogenic diet and beta-hydroxybutyrate (BHB) supplementation in people with Metastatic Renal Cell Carcinoma, run by Gustave Roussy, Cancer Campus, Grand Paris at 3 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study was stopped early (reason given: 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.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective response rate (time frame: at 8 weeks after diet initiation.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05119010, which also lists 64 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Dec 2024.

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KETOREIN Clinical Trial NCT05119010 | AzTrials