Fecal Microbiota Transplant and Pembrolizumab in Treating Patients with Stage III-IV Melanoma

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 are receiving combination ipilimumab with pembrolizumab or nivolumab are not eligible
• Must be pembrolizumab/nivolumab refractory/resistant – defined as having received at least 2 doses of pembrolizumab (or 2 doses of nivolumab) with documented systemic disease progression on staging imaging; progressive disease (PD) will be defined as increase in tumor burden > 20% relative to nadir (minimum recorded tumor burden) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1; 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 up to 1 year
• Patients with central nervous system (CNS) progression (parenchymal but not leptomeningeal) are eligible if CNS metastases are treated and deemed stable (with a repeat computed tomography [CT]/magnetic resonance imaging [MRI] imaging study) prior to the enrollment date; if radiation is used to treat CNS parenchymal disease, a 2 week washout period will apply
• 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/assent for the trial
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500 /mcL, performed within 14 days of treatment initiation
• Platelets >= 100,000 / mcL, performed within 14 days of treatment initiation
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment), performed within 14 days of treatment initiation
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN, performed within 14 days of treatment initiation
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN, performed within 14 days of treatment initiation
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases, performed within 14 days of treatment initiation
• Albumin >= 2.5 mg/dL, performed within 14 days of treatment initiation
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, performed within 14 days of treatment initiation
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, performed within 14 days of treatment initiation
• Female subject 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 subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
• Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

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 cerebrospinal fluid [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 required steroids 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 human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or active hepatitis B virus (HBV) and hepatitis C virus (HCV)
• Has an active infection requiring systemic therapy
• Has active human immunodeficiency virus (HIV) infection (as manifested by presence of HIV 1/2 antibodies and/or positive HIV enzyme-linked immunosorbent assay [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 (hepatitis [Hep] B - negative hepatitis B surface antigen [HBsAg] and HBV deoxyribonucleic acid [DNA]; Hep C – negative HCV ribonucleic acid [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
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• 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