PRIMARY OBJECTIVE:

I. To establish the effects of dietary intervention on the structure and function of the gut microbiome.

SECONDARY OBJECTIVES:

I. Assess the effects of dietary intervention on gut metabolic output and systemic metabolism.

II. Assess the effects of dietary intervention on systemic and tumor immunity. III. Determine the safety (adverse events [AEs]) and tolerability (Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome [GSRS-IBS]) of the dietary intervention.

IV. Assess the rate of immune related adverse events in patients on immunotherapy receiving dietary interventions.

V. Determine the maximum daily fiber content that 70% of participants are able to tolerate.

VI. 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).

VII. Assess the effects of dietary interventions on quality of life and other patient reported outcomes (PROs).

EXPLORATORY OBJECTIVES:

I. 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).

II. 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.

Inclusion Criteria:

• 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 sample
• Cohort-specific:
  • Unresectable:
    • Histologically confirmed unresectable stage III or stage IV melanoma
    • Currently receiving therapy with standard of care anti-PD1 immunotherapy. Initial induction with anti-CTLA4 and anti-PD1 is allowed
    • Stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as best response while on anti-PD1 >= 6 months for metastatic melanoma with plan to continue anti-PD1
    • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST version [v]1.1; i.e., defined as at least 1 lesion that can be accurately measured in at least 1 dimension [longest diameter to be recorded] with a minimum size of >= 10 mm by computerized tomography [CT] scan or caliper measurement on clinical exam)
      • Participants must have at least one lesion amenable to biopsy that has not been previously irradiated
      • Participants must be willing to undergo a newly-obtained core needle or incisional biopsy at baseline. Fine needle aspiration is not acceptable
  • Adjuvant:
    • Resected stage III/IV melanoma with planned initiation of adjuvant anti-PD1

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, bile acid sequestrants, 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