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.

NCT06896552 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 0046-25-RMC
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cancer; Immunotherapy; Ketogenic Diet

Keywords

Metastatic Melanoma; Renal Cell Carcinoma; Ketogenic Diet; Dietary Intervention and Immunotherapy; Ketogenic diet (KD) and cancer treatment

Outcome Measures

Primary Outcomes (3)

• Number of Participants Adhering to the Ketogenic Diet and Experiencing Treatment-Related Adverse Events as Assessed by CTCAE v5.0

  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

  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

  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 Outcomes (9)

• Overall response rate according to RECIST v1.

  End of treatment at 10 weeks

• Adherence to Dietary Interventions - Ketone Level Measurements

  Weekly from Baseline (Week 0) to Week 10

• Change in Body Weight (kg) Over the Study Period

  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)

  At enrollment (Baseline, Week 0) and at the end of treatment (Week 10).

• Fecal microbiome

  At enrollment (baseline) and at the end of treatment at 10 weeks

Study Arms (2)

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

EXPERIMENTAL

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

Standard Diet (SD) Group: A typical diet with no major changes.

NO INTERVENTION

Interventions

Ketogenic diet DIETARY_SUPPLEMENT

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.

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

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Rabin Medical Center: lead

Study Sites (1)

Rabin Medical Center

Petah Tikva, Israel

Location

Related Publications (1)

• 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

  BACKGROUND

MeSH Terms

Conditions

Neoplasms; Melanoma; Carcinoma, Renal Cell

Interventions

Diet, Ketogenic

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Diet, Carbohydrate-Restricted; Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Central Study Contacts

Keren Porper, M.Sc

CONTACT

97239377990; kerenporper83@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD Ph.D. MBA, Deputy Director of Rabin Medical Center, and Director of Davidoff Center Rabin Medical Center, Full Professor of Clinical Microbiology & Immunology at the Sackler Faculty of Medicine, Tel Aviv University.

Model Details: Single-center, open-label, prospective, non-randomized, controlled, sequential two-arm clinical trial

Study Record Dates

• First Submitted: March 5, 2025
• First Posted: March 26, 2025
• Study Start: April 1, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027
• Last Updated: March 26, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

IL (1)