Fecal Microbiota Transplant (FMT) in Melanoma Patients

Inclusion Criteria: * Have a histologically or cytologically confirmed diagnosis of unresectable stage III or IV melanoma. Patient may not have a diagnosis of uveal or mucosal melanoma. * Have received any number of prior systemic therapies for metastatic disease. Prior radiation therapy (any number) and interferon use (any formulation and/or duration) in the adjuvant or metastatic disease settings is permitted. Vaccine therapy will be counted as systemic therapy. * Patient must currently be receiving systemic PD-1 immunotherapy with pembrolizumab or nivolumab to be eligible. Patients who have received PD-1 immunotherapy in the adjuvant setting and then replaced are eligible. * Must be PD-1 inhibitor refractory/resistant - defined as having received at least 2 doses of pembrolizumab with documented systemic disease progression on staging imaging. PD will be defined as increase in tumor burden \> 20% relative to nadir (minimum recorded tumor burden) by RECIST v1.1. Once PD is confirmed, initial date of PD documentation will be considered as the date of disease progression. Patients can be enrolled at any time following initiation of PD-1 therapy assuming they have not had (at any time) a record of response to PD-1 therapy (prior best response of stable disease - acceptable; prior best response of complete/partial response - unacceptable). For patients receiving adjuvant PD-1 inhibitor therapy, initial date of PD documentation will be considered as the date of disease progression. * Patients with CNS progression (parenchymal but not leptomeningeal) are eligible if CNS metastases are treated and deemed stable (with a repeat CT/MRI imaging study) prior to the enrollment date. If radiation is used to treat CNS parenchymal disease, a 2 week washout period will apply (counted from Day 1 treatment). Stability must be confirmed with a repeat CT/MRI imaging study performed as part of the screening evaluation (at least 2 weeks after radiation). Patients with new CNS metastases identified during screening are ineligible. * Consent to receive FMT administered endoscopically (colonoscopically) and undergo necessary bowel preparation pre-procedure. * Understand infectious risks associated with FMT administration. Although FMT infusate has been screened for bacteria, viruses, fungi and parasites there is a risk of transmission of known and unknown infectious organisms contained in the donor stool. Post-FMT bacteremia (e.g. E. coli), sepsis and fatal events may rarely occur. * Understand non-infectious risks associated with FMT administration. Possible allergy and/or anaphylaxis to antigens in donor stool; theoretical risk of developing disease possibly related to donor gut microbiota including but not limited to: obesity, metabolic syndrome, cardiovascular disease, autoimmune conditions, allergic/atopic disorders, neurologic disorders, psychiatric conditions and malignancy. * Understand risks associated with colonoscopy including risk of infection transmission, colonic perforation, aspiration pneumonia, and death. * Understand that data regarding the long-term safety risk of FMT are lacking. * Consent to participate in the correlative studies and should have available tumor tissue for tumor biopsies. Acceptable biopsies include surgical biopsy, core biopsy or punch/surgical tumor biopsies (of accessible lesions). * Have measurable disease as per RECIST version 1.1. At least 1 of the tumor sites must be amenable to biopsy and this may not be the site of disease used to measure antitumor response. * Be willing and able to provide written informed consent for the trial. * Be 18 years of age or older on day of signing informed consent. * Have a performance status of 0 or 1 on the ECOG Performance Scale. * Demonstrate adequate organ function: Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) - ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases Albumin \>2.5 mg/dL International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * Female patients of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Female patients of childbearing potential must be willing to use an adequate method of contraception. Contraception, for the course of the study through 120 days after the last dose of study medication. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. * Male patients of childbearing potential must agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Exclusion Criteria: \- Presence of absolute contra-indications to FMT administration: Toxic megacolon Severe dietary allergies (e.g. shellfish, nuts, seafood) Inflammatory bowel disease Anatomic contra-indications to colonoscopy * Patients receiving PD-1 therapy whose disease is responding or stable (as defined by RECIST v1.1). * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. * Highly symptomatic patients (e.g., declining ECOG performance status; rapidly worsening symptoms; rapid progression of disease; progression of tumor at critical anatomical sites (e.g., spinal cord compression) requiring urgent alternative medical intervention) are not eligible. * Expected to require any other form of systemic or localized antineoplastic therapy while on study. * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (\> 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy prior to trial treatment. Patients receiving systemic steroids at physiologic doses are permitted to enroll assuming steroid dose is not above the acceptable threshold (\> 10 mg prednisone daily or equivalent). * Has a known history of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the patient has undergone potentially curative therapy with no evidence of that disease for five years. NOTE: The time requirement also does not apply to patients who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cancers including cervical cancer, breast cancer, melanoma, or other in situ cancers. * Active central nervous system (CNS) metastases and/or leptomeningeal involvement. Patients with treated brain metastases will be re-screened (MRI brain or CT head with IV contrast). Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI/CT for at least two weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids (≤ 10 mg/day prednisone or equivalent) for at least one weeks prior to enrollment. Patients with leptomeningeal disease (leptomeningeal enhancement on MRI/CT imaging and/or positive CSF cytology) are not eligible to enroll. Patients with no history of CNS disease will not require a repeat MRI brain unless they have symptoms to suggest new brain metastases. * Had a severe hypersensitivity reaction to treatment with pembrolizumab or any of its excipients. * Has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo, type I diabetes, resolved childhood asthma/atopy are exceptions to this rule. Patients who require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Patients with hypothyroidism stable on hormone replacement are not excluded from the study. * Has a history of (non-infectious) pneumonitis that was life-threatening and/or required invasive support (CTCAE grade 4 or greater) or current pneumonitis. * Has serious concomitant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or restrictive pulmonary diseases, active systemic infections, and inflammatory bowel disorders. This includes HIV or AIDS-related illness, or active HBV and HCV. * Has an active infection requiring systemic therapy. * Has active COVID-19 infection and/or exposure to SARS-CoV-2 defined as Positive SARS-CoV-2 result on nasopharyngeal and/or stool specimens (by RT-PCR test), Active COVID-19 infection (per CDC guidelines), Exposure to active COVID-19 infected patient (as confirmed using SARS-CoV-2 RT-PCR test or other approved test) as defined per CDC guidelines * Has active human immunodeficiency virus (HIV) infection (as manifested by presence of HIV 1/2 antibodies and/or positive HIV ELISA/Western Blot assays). * Has active Hepatitis B or Hepatitis C infection. Patients with a history of Hepatitis B/C infection who have received anti-viral therapy and are disease free (Hep B - negative HBsAg and HBV DNA; Hep C - negative HCV RNA) may be considered for enrollment after discussion with Principal Investigator. * Has a known history of active TB (Bacillus Tuberculosis). * Patient has received a live vaccine within 4 weeks prior to the first dose of treatment. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. * Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Patients with prior adverse events on replacement therapy who are asymptomatic or minimally symptomatic are not excluded from the study (i.e. hypothyroidism, hypopituitarism, adrenal insufficiency). * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.