Fecal Microbiota Transplant (FMT) in Melanoma Patients
Fecal Microbiota Transplant (FMT) in Melanoma Patients
The main goal of this research study is to determine if the fecal microbiota transplant (FMT)
 improves the body's ability to fight your cancer.
This is a phase II Simon two-stage single-center study of concurrent fecal microbiota
 transplang (FMT) with pembrolizumab in patients with PD-1 resistant/refractory melanoma. The
 study will be conducted over a 12-week period (and up to 24-weeks in responding patients).

 Patient eligibility is based upon prior exposure to PD-1 inhibitor therapy and response at
 first (or subsequent) restaging scans from week 12 up to week 52. Patients must have received
 a minimum of 2 cycles to be considered eligible. Patients who have received either nivolumab
 or pembrolizumab are eligible. Patients who have received pembrolizumab/nivolumab in
 combination with other investigational agent(s) may be eligible at the discretion of the
 treating investigator. PD-1 refractory disease is defined as progressive disease (PD) at the
 first (or subsequent) radiographic evaluation while receiving PD-1 inhibitor treatment as
 assessed by RECIST v1.1 on a restaging scan. Other eligibility criteria include absence of
 CNS disease, presence of disease amenable to biopsy and lack of contra-indications to FMT
 administration. Patients will be stratified on the presence or absence of liver metastases.

 Suitable patients will be identified following first (or subsequent) restaging study that
 documents progressive disease (RECIST v1.1). Patients will undergo a screening evaluation
 consisting of imaging (including CNS if clinically suspected), tumor biopsy, and
 serological/stool studies to confirm suitability for FMT administration. Eligible patients
 will receive FMT endoscopically (along with intestinal biopsy) (with cycle 1 pembrolizumab
 +/- 3 days) followed by 3 further cycles of pembrolizumab (cycles 2-4) following which
 restaging will be performed. Patients with stable and/or responding disease will continue to
 receive pembrolizumab on study for 4 cycles. Patients with stable and/or responding disease
 after 8 cycles of pembrolizumab will continue to receive therapy off study until disease
 progression or up to two years from FMT administration.
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.