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

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • 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 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

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
Intervention / Treatment
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

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

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

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)

April 1, 2025

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

April 1, 2027

Study Registration Dates

First Submitted

March 5, 2025

First Submitted That Met QC Criteria

March 19, 2025

First Posted (Actual)

March 26, 2025

Study Record Updates

Last Update Posted (Actual)

March 26, 2025

Last Update Submitted That Met QC Criteria

March 19, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Other Study ID 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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