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

December 3, 2024 updated by: Gustave Roussy, Cancer Campus, Grand Paris
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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75015
        • Hôpital Européen Georges Pompidou
      • Paris, France, 75679
        • Hôpitaux Cochin-Port-Royal
    • Val-de-Marne
      • Villejuif, Val-de-Marne, France, 94805
        • Gustave Roussy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
at 8 weeks after diet initiation.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
from the first day of diet and up to 2 years from diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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).
from the first day of diet and up to 2 years from diet initiation
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.
At screening and 9 weeks after diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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.
from the first day of diet and up to 2 years from diet initiation
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 data.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

Investigators

  • Principal Investigator: Emeline COLOMBA BLAMEBLE, MD, Gustave Roussy, Cancer Campus, Grand Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 24, 2023

Primary Completion (Actual)

May 22, 2024

Study Completion (Actual)

May 22, 2024

Study Registration Dates

First Submitted

October 21, 2021

First Submitted That Met QC Criteria

November 3, 2021

First Posted (Actual)

November 12, 2021

Study Record Updates

Last Update Posted (Estimated)

December 5, 2024

Last Update Submitted That Met QC Criteria

December 3, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2020-A03550-39
  • 2020/3206 (Other Identifier: CSET number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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