Single-Center Trial on Ketogenic Diet and Immunotherapy in Advanced Cancer This Study Evaluates the Safety and Effects of a Ketogenic Diet (KD) Combined With Immunotherapy in Adults With Advanced Melanoma, cSCC, or RCC.

March 19, 2025 updated by: Gal Markel, Rabin Medical Center

Investigating the Effect of Ketogenic Diet on Immunological Parameters in Advanced Cancer Patients Undergoing Immunotherapy

This clinical trial aims to evaluate whether a ketogenic diet (KD), when combined with immunotherapy, can improve immune function and treatment outcomes in patients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), or renal cell carcinoma (RCC).

Why Is This Study Important? Immunotherapy is a promising cancer treatment, but not all patients respond well. Research suggests that diet, particularly a high-fat, low-carbohydrate ketogenic diet, may help boost the immune system and make treatments more effective.

What Will This Study Examine?

Researchers want to understand:

Is the ketogenic diet well-tolerated for cancer patients? Does the diet improve immune responses and treatment effectiveness?

How Will the Study Work?

Participants will be placed into one of two groups:

Ketogenic Diet (KD) Group: A structured high-fat, low-carb diet (intermittent schedule: 2 weeks on, 1 week off).

Standard Diet (SD) Group: A typical diet with no major changes. Throughout the study, a dietitian will closely support and guide you. Both groups will continue their standard immunotherapy treatment.

What Will Participants Do? Write their food intake three times a week to help assess dietary adherence Follow their assigned diet for 10 weeks Have weekly check-ins with a dietitian (in-person at the hospital or via phone) Have weekly blood glucose and ketone level checks using a home device. Provide monthly blood samples to measure immune response during routine immunotherapy infusions Provide stool samples for gut microbiome analysis at the start and end of the study Measure Monthly Weight, body composition, and resting calorie burn Complete quality-of-life questionnaires

What Are the Potential Benefits? Improved response to immunotherapy Better understanding of how diet influences cancer treatment Potential for a new supportive strategy for cancer care

This study may help uncover ways to enhance cancer treatment through personalized nutrition.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

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

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • • Males and females, age >= 18 years

    • Patients with a histologically confirmed melanoma or cSCC or RCC receiving first line treatment with combination nivolumab and ipilimumab /relatlimab or single agent ipilimumab, nivolumab, pembrolizumab, Cemiplimab.
    • Able to read, understand, and provide written informed consent
    • Willing and able to complete all study-specific procedures and visits
    • Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

    • Blood tests:

      • Creatinine (Cr) < 1.5 mg/dL.
      • Magnesium normal range ( 1.5 -2,6 mg/dL)
      • Liver function tests (LFTs) 2.5x upper limit of normal (ULN).
      • Neutrophils ≥ 1,000/mm3, platelets ≥ 50,000/mm3, Hb>8 g/dL
      • Women of childbearing potential must have a negative β-HCG pregnancy test documented within 1 week of registration.

Exclusion Criteria:

  • • Individuals < 18 years of age

    • Unable or unwilling to provide consent
    • Other active malignancy (other than adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or any other cancer from which the patient has been disease free >=2 years)
    • Currently consuming a low-carbohydrate (< 130 g/day) or KD or done so in the last 6-months
    • Patients currently participating in an interventional or therapeutic clinical trial involving the use of active anti-cancer therapy.
    • Active autoimmune diseases requiring active Immune suppressive medications
    • Systemic steroid therapy, excluding for replacement due to adrenal insufficiency
    • Major surgery within last 3 months
    • BMI <18 or >35
    • Medical contraindications to the intervention diet as determined by the treating physician.
    • Self-reported major dietary restrictions related to the intervention such as irritable bowel syndrome (IBS).
    • Patients with a history or active eating disorder
    • Uncontrolled Diabetes mellitus or patients receiving insulin
    • Known diagnosis of HIV
    • Known active hepatitis B or hepatitis C
    • Known inborn errors of lipid metabolism
    • Sever or uncontrolled Hyperlipidemia (total cholesterol over 400 mg / dL, low-density lipoprotein (LDL) above 300 mg / dL, triglycerides over 500 mg / dl.).
    • Pregnant or lactating.
    • Patients who have undergone a transplant

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: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Ketogenic Diet (KD) Group: A high-fat, low-carb diet (intermittent schedule: 2 weeks on,1 week off))
Seven days (±2 days) before first dose of immunotherapy, patients will receive instructions to follow KD. The KD composition: 5-10% of the calories from carbohydrate, 20-30% protein and 60-70% fat. No calorie restriction will be applied, and patients will be instructed to eat to satiety. Supplemental MCT (medium chain triglyceride) oil or /and ketocal powder (Nutricia) will be added at the dietician's discretion in order to promote ketone production. During the period off the KD, the participants will be instructed to gradually follow standard diet composition (50-60% of the calories from carbohydrate, 15-20% protein and 20-30% fat). Diet protocol will be given to the patient along with specific menu suggestions for each individual.
Dietary supplement: Ketogenic diet
Ketogenic Diet as an Adjunct to Immunotherapy: Unlike many trials focused on chemotherapy or targeted therapies, this study specifically investigates the synergistic effects of the ketogenic diet with immune checkpoint inhibitors (ICIs), a promising approach for enhancing immunotherapy efficacy. The diet's high-fat, low-carbohydrate regimen is designed to shift metabolism towards ketone bodies and fatty acid utilization, potentially modulating immune responses and tumor immunogenicity in a way that standard diets do not.
No Intervention: Standard Diet (SD) Group: A typical diet with no major changes.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of Participants Adhering to the Ketogenic Diet and Experiencing Treatment-Related Adverse Events as Assessed by CTCAE v5.0
Time Frame: From enrollment to the end of treatment at 10 weeks

This measure will assess the feasibility and tolerability of the ketogenic diet (KD) in cancer patients undergoing immunotherapy by evaluating:

Diet Adherence: The number of participants who maintain KD for at least 80% of the study duration, based on dietary intake logs and ketone level measurements.

Tolerability: The number of participants experiencing treatment-related adverse events (AEs), as assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The severity and frequency of AEs will be documented and categorized.
From enrollment to the end of treatment at 10 weeks
Change in Peripheral Blood Mononuclear Cell (PBMC) Composition at Baseline, During, and Post-Intervention
Time Frame: Monthly (week 0, 4, 10 ±1 week).

This measure will evaluate changes in immune cell composition in response to the ketogenic diet (KD) and immunotherapy.

PBMC Composition: Assessed using cytometry by time-of-flight (CyTOF) to characterize shifts in immune cell subsets (e.g., T cells, natural killer cells, monocytes).

Data Analysis: Changes from the baseline will be reported as absolute values and fold-changes over time.
Monthly (week 0, 4, 10 ±1 week).
Serum Cytokine Levels at Baseline, During, and Post-Intervention
Time Frame: Monthly (week 0, 4, 10 ±1 week).

This measure will evaluate changes in cytokine levels in response to the ketogenic diet (KD) and immunotherapy.

Serum Cytokine Levels: Quantified using multiplex immunoassays to measure the concentrations of key cytokines, such as IL-2, IFN-γ, TNF-α, and IL-10.

Data Analysis: Changes from baseline will be reported as absolute values and fold-changes over time.
Monthly (week 0, 4, 10 ±1 week).

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall response rate according to RECIST v1.
Time Frame: End of treatment at 10 weeks
End of treatment at 10 weeks
Adherence to Dietary Interventions - Ketone Level Measurements
Time Frame: Weekly from Baseline (Week 0) to Week 10

Ketone Level Measurements: Ketone levels will be measured to assess whether participants are in a state of ketosis (>0.3 Mm), indicating adherence to the ketogenic diet.

Data Analysis: Ketone levels will be analyzed to determine adherence to the ketogenic diet.
Weekly from Baseline (Week 0) to Week 10
Change in Body Weight (kg) Over the Study Period
Time Frame: Baseline (Week 0), Week 4, Week 10, and Week 14 (±1 week).
Body weight (in kilograms) will be measured using a calibrated digital scale at specified time points. Changes from baseline will be reported as absolute weight differences and percentage change
Baseline (Week 0), Week 4, Week 10, and Week 14 (±1 week).
Change in Quality of Life Score Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
Time Frame: At enrollment (Baseline, Week 0) and at the end of treatment (Week 10).

Quality of life will be assessed using the EORTC QLQ-C30 questionnaire, a validated tool for measuring cancer patients' health-related quality of life.

The EORTC QLQ-C30 consists of 30 items, evaluating functional scales (physical, role, emotional, cognitive, and social functions), symptom scales (fatigue, pain, nausea/vomiting, etc.), and global health status.

Scores range from 0 to 100. Higher scores on functional and global health scales indicate better quality of life.

Higher scores on symptom scales indicate greater symptom burden (worse outcome).

Changes from baseline to Week 10 will be reported as mean score differences.
At enrollment (Baseline, Week 0) and at the end of treatment (Week 10).
Fecal microbiome
Time Frame: At enrollment (baseline) and at the end of treatment at 10 weeks
Such as, but not limited to, 16S analysis
At enrollment (baseline) and at the end of treatment at 10 weeks
Sarcopenia
Time Frame: At enrollment (baseline) and at the end of treatment at 10 weeks
Assessed using CT scans of the axial L3 sections and customized software
At enrollment (baseline) and at the end of treatment at 10 weeks
Body composition-- Fat Mass and Lean Mass
Time Frame: Monthly (week 0, 4, 10 ±1 week).

This measure will assess changes in body composition using bioelectrical impedance analysis (BIA).

Fat Mass(kg) and Lean Mass (kg): Body composition will be assessed using Bioelectrical Impedance Analysis (BIA) to measure fat mass(kg) and lean mass(kg).

Data Analysis: Changes in fat mass and lean mass will be reported as absolute values and fold-changes over time.
Monthly (week 0, 4, 10 ±1 week).
Resting Energy Expenditure (REE)
Time Frame: Monthly (week 0, 4, 10 ±1 week).
Measured by indirect calorimeter - Q-NRG
Monthly (week 0, 4, 10 ±1 week).
The Rate of immune-related adverse events
Time Frame: From enrollment to the end of treatment at 10 weeks
From enrollment to the end of treatment at 10 weeks

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Rabin Medical Center

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

  • 1. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-1355. 2. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39. 3. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2(5):e192535. 4. Golonko A, Pienkowski T, Swislocka R. Dietary factors and their influence on immunotherapy strategies in oncology: A comprehensive review. Cell Death Dis. 2024;15:254. 5. Weber DD, Aminzadeh-Gohari S, Tulipan J, Feichtinger RG. Ketogenic diet in cancer therapy. Aging (Albany NY). 2020;12(3):6018. 6. Klement RJ. The emerging role of ketogenic diets in cancer treatment. Curr Opin Clin Nutr Metab Care. 2017;20(1):28-34. 7. Harel M, Ortenberg R, Varanasi SK, Mangalhara KC, Mardamshina M, Markovits E, et al. Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence. Cell. 2019;179:236-250.e218. 8. Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight. 2021;6(2):e145207. 9. Jiang T, Zhou C, Ren S. Role of IL-2 in cancer immunotherapy. Oncoimmunology. 2016;5(6):e1163462. 10. Erickson N, Boscheri A, Linke B, Huebner J. Systematic review: Isocaloric ketogenic dietary regimes for cancer patients. Med Oncol. 2017;34(5):72. 11. Woolf EC, Curley KL, Liu Q, Scheck AC. The ketogenic diet alters the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential, and vascular permeability in a mouse glioma model. PLoS One. 2015;10:e0130357. 12. Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer - Where do we stand? Mol Metab. 2020;33:102-121. 13. Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer. 2016;16:310. 14. Rom-Jurek EM, Kirchhammer N, Ugocsai P, Ortmann O, Wege AK, Brockhoff G. Regulation of programmed death ligand 1 (PD-L1) expression in breast cancer cell lines in vitro and in immunodeficient and humanized tumor mice. Int J Mol Sci. 2018;19:563. 15. Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: Effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191:1486-1495. 16. Weber DD, Aminzadeh-Gohari S, Thapa M, Kofler B, Feichtinger RG. Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity. Cancer Metab. 2022;10:12. 17. Russo E, Nannini G, Amedei A. Exploring the food-gut axis in immunotherapy response of cancer patients. World J Gastroenterol. 2020;26(33):4919-4932. 18. Verhoog S, Taneri PE, Roa Diaz ZM, Marques-Vidal P, Troup JP, Bally L, et al. Dietary factors and modulation of bacteria strains of Akkermansia muciniphila and Faecalibacterium prausnitzii: A systematic review. Nutrients. 2019;11:1565. 19. Murphy S, Rahmy S, Gan D, Gao Y, Jiang H, Alves MR, et al. Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy. Cancer Res. 2024;84(10):1597-1612. 20. Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, et al. Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell. 2017;32:377-391.e379. 21. NutRatio.com NutRatio [Internet]. [cited 2022 Nov 24]. Available from: https://nutratio.com/ 22. Römer M, Dörfler J, Huebner J. The use of ketogenic diets in cancer patients: A systematic review. Clin Exp Med. 2021;21(4):501-536

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 (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 5, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 19, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 26, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 26, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 19, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 0046-25-RMC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

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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