Clinical Study on High-fiber Diet and Short-term Fasting in Melanoma Under Immunotherapy With Checkpoint Inhibition

• High-Fiber Diet (Behavioral): High-Fiber Diet (>35g/day) according to the German Nutrition Society (Deutsche Gesellschaft für Ernährung, DGE) for 6 months.
• High-Fiber Diet and Short-Term Fasting (Behavioral): High-Fiber Diet (>35g/day) according to the German Nutrition Society (Deutsche Gesellschaft für Ernährung, DGE) and 72 hours of short-term fasting (max 400kcal/day) with every immunetherapy cycle for 6 months.

Primary outcomes

• Study feasability, measured by adequacy and efficiency of recruitment strategies [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Number of participants recruited per month (at least 2 per month)
• Study feasability, measured by adherence to the intervention and dropout rate [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Adherence to the Intervention for intervention groups (at least 70% of the fasting cycles)
• Study feasability, measured by acceptability of study outcome measures [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Patient acceptability of study assessments (number of completed study visits)
• Feasibility of the study procedures [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Feasibility of study procedures, e.g. in terms of patient and provider acceptance of randomisation and outcome measures (percentage of eligible participants who explicitly refuse to participate because of the randomization process, missing item-level data, completion rates of questionnaires)
• Feasibility of the intervention procedures [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Feasibility of the intervention methods (including patient acceptance of video and telephone consultations measured by no-show rate, patient safety in terms of number of adverse events)

Secondary outcomes

• Adverse events [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Frequency and severity of treatment-emergent adverse events during the study
• Hospitalizations rate [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Number of hospital admissions occurring during the study period
• Dose Interruption or reduction [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Frequency of dose interruption or reduction
• Cumulative dose [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Total cumulative dose of study treatment administered during the study period
• Treatment discontinuation [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Frequency of treatment discontinuation and the reasons for it
• Subjective Severity of the main symptom [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Patient-reported severity of the main symptom assessed using a Visual Analog Scale (VAS) ranging from 0 (no symptoms) to 100 (worst imaginable symptom severity)
• Distress Thermometer [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Psychological distress assessed using the Distress Thermometer, a self-report scale ranging from 0 (no distress) to 10 (extreme distress). The DT is accompanied by a Problem list that identifies practical, family, emotional, spiritual/religious, and physical concerns
• Health status (EQ-5D-5L) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Health status assessed using the EQ-5D-5L questionnaire. It evaluates five dimensions (mobilty, self-care, usual activities, pain/discomfort, and anxiety/depression, each rated at five levels (no problems, slight problems, moderate problems, severe problems and extreme problems).
• Short Form 36 [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Change in health-related quality of life assessed using the Short Form-36 (SF-36). The instrument evaluates eight domains of physical and mental health, with higher scores indicating better quality of life (scale 0-100).
• Quality of life of cancer patients (EORTC QLQ-C30) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Quality of life of cancer patients assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The instrument comprises 30 items evaluating global health status/quality of life, functional domains (physical, role, emotional, cognitive, and social functioning), and symptom domains. Higher scores on functional and global health status scales indicate better functioning and quality of life, whereas higher symptom scores indicate greater symptom burden.
• Nutrition [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Dietary intake assessed using a 3-day food diary and using a validated Food Frequency Questionnaire (FFQ). The questionnaire evaluates the usual frequency of consumption of a range of food and beverage items over the specified recall period. Data are used to characterize dietary patterns and estimate intake of major food groups and nutrients.
• Differential blood count [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Analysis of differential blood count to determine the distribution of leukocyte subtypes, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils." Unit of Measure: cells/µL
• C-reactive protein (CRP) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: CRP (C-reactive protein) as a marker of inflammatory conditions is used to assess acute inflammation and monitor the effects of prolonged fasting and plant-based nutrition. Higher scores indicate more inflammation. Serum CRP, unit of Measure: CRP in milligram per liter (mg/L)
• Alanine aminotransferase (ALT/ALAT) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Alanine aminotransferase (ALT/ALAT), Unit of Measure: U/L
• Aspartate aminotransferase (AST/ASAT) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Aspartate aminotransferase (AST/ASAT), unit of Measure: U/L
• Electrolytes [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: calcium in millimol per liter (mmol/L), potassium (mmol/L), sodium (mmol/L)
• Creatinine [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Creatinine in µmol per liter (µmol/L), Biomarker of renal function and muscle metabolism
• Glucose [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Glucose, unit of Measure: mg/dL oder mmol/L
• Lactate dehydrogenase (LDH) [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Lactate dehydrogenase (LDH), unit of Measure: U/L
• S100 protein [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: S100 protein, unit of Measure: µg/L or ng/mL

Other outcomes

• Waist circumference [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Waist circumference, unit of Measure: cm
• Hip circumference [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Hip circumference, unit of Measure: cm
• Bioimpedance measurement [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Body composition assessed by bioelectrical impedance analysis (BIA)
• Psoas muscle density [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Psoas muscle density assessed from clinically indicated CT scans when available from standard clinical care
• Progression-free survival (PFS) [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Time from study entry to disease progression or death
• Recurrence-free survival (RFS) [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Time from study entry to disease recurrence or death
• Overall survival (OS) [After 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Time from study entry to death from any cause
• Flow cytometry [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Immune cell subsets quantified by flow cytometry
• Ketone bodies [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Ketone body concentration, Indicators of fat metabolism and ketosis, analyzed for metabolic adaptations. Unit of Measure: mmol/L
• Cytokine profile [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Quantification of pro- and anti-inflammatory cytokines (e.g., IL-6, IL-17, TNF-α, IL-10) using multiplex ELISA or Luminex technology.
• Immune cell proliferation and Stimulated cytokine production [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Functional immune cell tests: Proliferation assays and cytokine production following stimulation
• Gut microbiota diversity [Baseline, after 6 weeks, after 3 months, after 6 months, optional follow-ups at 12 and 18 months]: Gut microbiota diversity assessed by shotgun metagenomic sequencing of stool samples.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically or cytologically confirmed stage IIB-IIIC melanoma
* Indication for immune checkpoint inhibition as monotherapy as determined by the tumor board
* No prior systemic melanoma therapy
* ECOG 0 or 1
* ≥ 18 years of age

Exclusion Criteria:

* Pregnancy or breastfeeding
* Underweight (BMI ≤19.5)
* Pre-existing eating disorder
* Severe internal medical conditions (e.g., renal insufficiency with creatinine > 2 mg/dL) or secondary malignancy
* Current vegan diet or prolonged fasting (≤ 4 days) within the last 6 months
* Use of antibiotics within 4 weeks prior to the start of the study intervention

• Anika Rajput, MD/PhD, Principal investigator, Charité - Universitätsmedizin Berlin, Department of Dermatology, Venerology and Allergology