Clinical trial NCT06896552: 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.
Official title: Investigating the Effect of Ketogenic Diet on Immunological Parameters in Advanced Cancer Patients Undergoing Immunotherapy
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Cancer
Immunotherapy
Ketogenic Diet
Keywords: Metastatic Melanoma
Renal Cell Carcinoma
Ketogenic Diet
Dietary Intervention and Immunotherapy
Ketogenic diet (KD) and cancer treatment
Lead sponsor: Rabin Medical Center
Sponsor class: OTHER
First posted: 2025-03-26
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Single-center, open-label, prospective, non-randomized, controlled, sequential two-arm clinical trial
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Adhering to the Ketogenic Diet and Experiencing Treatment-Related Adverse Events as Assessed by CTCAE v5.0
timeFrame: From enrollment to the end of treatment at 10 weeks
measure: Change in Peripheral Blood Mononuclear Cell (PBMC) Composition at Baseline, During, and Post-Intervention
timeFrame: Monthly (week 0, 4, 10 ±1 week).
measure: Serum Cytokine Levels at Baseline, During, and Post-Intervention
timeFrame: Monthly (week 0, 4, 10 ±1 week).
Secondary outcomes:
measure: Overall response rate according to RECIST v1.
timeFrame: End of treatment at 10 weeks
measure: Adherence to Dietary Interventions - Ketone Level Measurements
timeFrame: Weekly from Baseline (Week 0) to Week 10
measure: Change in Body Weight (kg) Over the Study Period
timeFrame: Baseline (Week 0), Week 4, Week 10, and Week 14 (±1 week).
measure: Change in Quality of Life Score Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
timeFrame: At enrollment (Baseline, Week 0) and at the end of treatment (Week 10).
measure: Fecal microbiome
timeFrame: At enrollment (baseline) and at the end of treatment at 10 weeks
measure: Sarcopenia
timeFrame: At enrollment (baseline) and at the end of treatment at 10 weeks
measure: Body composition-- Fat Mass and Lean Mass
timeFrame: Monthly (week 0, 4, 10 ±1 week).
measure: Resting Energy Expenditure (REE)
timeFrame: Monthly (week 0, 4, 10 ±1 week).
measure: The Rate of immune-related adverse events
timeFrame: From enrollment to the end of treatment at 10 weeks
Other outcomes:
Locations:
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
Study officials:
References:
citation: 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