Effect of Diet on the Immune System in Patients With Stage III-IV Melanoma Receiving Immunotherapy, DIET Study

Study Overview
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Brief Summary
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This phase II trial investigates the possible immune effects of two different diets targeting the gut microbiome in patients with stage III-IV melanoma that has been removed by surgery (resectable), has spread to other places in the body (metastatic), or is unable to be removed by surgery (unresectable), and who are being treated with the immunotherapy drugs pembrolizumab or nivolumab as part of their standard of care. Both diets are whole foods diets that meet the American Cancer Society recommendations for cancer patients, but they will vary in fiber content. The purpose of this trial is to learn about the effects of dietary interventions on the structure and function of the gut microbiome in patients with melanoma being treated with standard of care immunotherapy (pembrolizumab or nivolumab).

Detailed Description
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PRIMARY OBJECTIVE: To establish the effects of dietary intervention on the structure and function of the gut microbiome. SECONDARY OBJECTIVES: Assess the effects of dietary intervention on gut metabolic output and systemic metabolism. Assess the effects of dietary intervention on systemic and tumor immunity Determine the safety (AEs) and tolerability (GSRS-IBS) of the dietary intervention Assess the rate of immune related adverse events in patients on immunotherapy receiving dietary interventions Determine the maximum daily fiber content that 70% of participants are able to tolerate Assess the adherence to the dietary interventions as defined by 70% of calories consumed over the duration of the study being derived from provided diets (as measured by food records) Assess the effects of dietary interventions on quality of life and other patient reported outcomes (PROs) EXPLORATORY OBJECTIVES: Assess the association of dietary interventions with clinical outcomes (objective response rate [ORR] and progression-free survival [PFS] rate in unresectable cohort and recurrence rate [RR] in adjuvant cohort). Explore predictors of biological response to dietary interventions. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (ISOCALORIC HIGH-FIBER DIET): Patients receive a whole foods diet that follows the recommended American Cancer Society guidelines but is higher in fiber for 11 weeks. ARM II (ISOCALORIC CONTROL DIET): Patients receive a standard whole foods diet of recommended by the American Cancer Society for 11 weeks. After completion of study, patients are followed up at 12 weeks.

Official Title
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Diet and Immune Effects Trial: DIET- A Randomized Double Blinded Dietary Intervention Study in Patients With Metastatic Melanoma Receiving Immunotherapy

Conditions
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Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma, Pathologic Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Unresectable Melanoma

Intervention / Treatment
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* Other: Dietary Intervention
* Other: Dietary Intervention
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old. Body mass index (BMI) 18.5-40 kg/m^2 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 English-speaking Self-reported willingness to exclusively eat the provided diets Self-reported willingness to comply with scheduled visits, undergo venipuncture, and provide stool samples Cohort-specific: 1 Adjuvant Melanoma: i. Resected Stage II-IV melanoma with planned initiation of adjuvant anti-PD1 +/- anti-CTLA4 or anti-LAG3 2 Unresectable Melanoma: i. Histologically confirmed unresectable stage III or Stage IV melanoma with planned initiation of standard of care anti-PD1 +/- CTLA4 or anti-PD1 +/- LAG3 immunotherapy and no prior immunotherapy in the metastatic setting. 3 Neoadjuvant Melanoma: i. Histologically confirmed stage III/IV melanoma with planned initiation of neoadjuvant anti-PD1 +/- anti-CTLA4 or anti-LAG3 1. Participants must have archival tissue block available or be willing to undergo a newly-obtained core needle or incisional biopsy at baseline. Fine needle aspiration is not acceptable. 4 Unresectable RCC: i. Unresectable clear-cell renal cell carcinoma with planned initiation of standard of care anti-PD1 +/- anti-CTLA4 immunotherapy Exclusion Criteria: History of >= grade II colitis or diarrhea on immunotherapy or any ongoing colitis or diarrhea of any grade Unresolved >= grade III immune-related adverse event on immunotherapy (other than endocrinopathy requiring hormone replacement) History of active inflammatory bowel disease or major gastrointestinal surgery (not including appendectomy or cholecystectomy) within 3 months of enrollment or any history of total colectomy, or bariatric surgery (bariatric surgery which does not disrupt the gastrointestinal lumen, i.e. restrictive procedures such as banding, are permitted). Medical contraindications to intervention diet as determined by the treating physician Self-reported major dietary restrictions related to the intervention Diagnosis of diabetes mellitus type I or type II that requires medical treatment or random glucose > 200 mg/dL Antibiotic use within 21 days of planned start of equilibration diet (self-reported and/or noted by the treating physician) Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study intervention administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease Regularly taking probiotics, fiber supplements, or any other medication or supplement that could affect study outcome as determined by the principal investigator and unable/unwilling to discontinue for the purpose of the study. These agents must be discontinued at least 14 days prior to start of diet Currently consuming an average estimated daily fiber intake exceeding 20 grams based on the results of the preliminary dietary assessment; vegetarian or vegan Current smoker or heavy drinker (defined as > 14 drinks per week) or current self reported illicit drug use Uncontrolled concurrent illness or infection or psychiatric illness/social situations that would limit compliance with study requirements Unable or unwilling to undergo study procedures Plan for travel during the study that would preclude adherence to prescribed diets

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (isocaloric high-fiber diet)<br>Patients receive a whole foods diet that follows the recommended American Cancer Society guidelines but is higher in fiber for 11 weeks. | Other: Dietary Intervention<br>* Consume isocaloric whole foods diet higher in fiber<br>* Other names: Nutritional Interventions;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Active Comparator: Arm II (isocaloric diet)<br>Patients receive a standard whole foods diet recommended by the American Cancer Society for 11 weeks. | Other: Dietary Intervention<br>* Whole foods diet<br>* Other names: Nutritional Interventions;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the gut microbiome | Changes of alpha-diversity (e.g., Shannon index) and abundance/relative abundance of different taxon levels (e.g., genus, family), from baseline to end of intervention, will be estimated. The outcomes will be compared. between two arms using t-test or Mann-Whitney test. Linear mixed effects models will be used for assessing the longitudinal data. Similarity in microbiome community structure will be assessed using principal coordinate analysis (PCoA) and compared using multivariate analysis of variance (MANOVA). | Baseline up to 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in systemic and tumor immunity | Percent change in CD8 T cells using flow cytometry will be compared between two arms using t-test or Mann-Whitney test. Pearson or Spearman correlation coefficient will be used to assess the correlation between the outcome at baseline and end of intervention. | Up to 12 weeks | 
| Change in metabolic profile | Change in relative concentration (ion intensity determined as area under the curve) measured by mass spectrometry-based analysis of blood and fecal specimens from baseline to end of intervention will be compared between two arms using t-test or Mann-Whitney test. | Baseline up to 11 weeks | 
| Change in quality of life (QOL) | Change in quality of life between baseline and end of intervention using a validated, 30 question scoring instrument (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Each question is scored in from 1 (not at all) to 4 (very much) in a Likert format. Linear mixed effects models will be used for assessing the longitudinal data. Pearson or Spearman correlation coefficient will be used to assess the correlation between measures for quality of life at baseline and end of intervention. | Baseline up to 11 weeks | 
| Incidence of adverse events | AEs attributed to diet as well as immune-related adverse events (irAEs) attributed to immunotherapy will be assessed using frequency counts and percentages. | Up to 12 weeks | 
| Symptom profile | To assess gastrointestinal symptoms related to the dietary interventions, the GSRS-IBS will be used. The GSRS-IBS is a 13-item validated instrument with subscales for each item ranging from 0 (no discomfort at all) to 7 (very severe discomfort). The gastrointestinal symptoms (GSRS-IBS) will be summarized using frequency counts and percentages. | Up to 12-week follow-up |