Oral Restorative Microbiota Therapy to Improve Diarrhea in Solid Tumor Cancer Patients with Refractory Immune-Mediated Diarrhea and Colitis

Inclusion Criteria

• Localized, locally advanced or metastatic solid tumors who have received at least two doses of immune checkpoint inhibitor (ICI) (PD-1/PD-L1 with or without CTLA-4 inhibitor)
• ICI used as a single agent, or combination or ICI in combination with other cytotoxic chemotherapy or targeted therapy for curative or palliative intent treatment
• Last ICI treatment with in 6 weeks of onset of IMDC symptoms
• Meet one of the criteria for steroid refractory IMDC defined as: * Persistent symptoms (NCI CTCAE v 5.0 grade ≥ 2 diarrhea) following high-dose corticosteroid therapy (≥ 1 mg/kg/day prednisone or equivalent) for least 48 hours or * Persistent symptoms (ongoing grade ≥ 2 diarrhea per CTCAE v5.0.) following use of a one or more biologic agent (i.e. either a tumor necrosis factor-alpha [TNFα] inhibitor or an anti-integrin) in addition to corticosteroids (with starting dose of prednisone or equivalent ≥ 1 mg/kg/day for at least 48 hours followed by receipt of at least one dose of either a TNFα inhibitor or an anti-integrin for at least 48 hours or * For patients with relapsed IMDC who have discontinued steroids: Relapsed IMDC symptoms for 24 or more hours (NCI CTCAE v 5.0 grade ≥ 2 diarrhea) within 4 weeks of discontinuing prednisone or equivalent. These patients should have received initial high-dose corticosteroid therapy (≥ 1 mg/kg/day prednisone or equivalent) with subsequent taper over at least 4 weeks or * For patients with relapsed IMDC following the tapering of steroids relapsed IMDC symptoms for 24 or more hours (NCI CTCAE v 5.0 grade ≥ 2 diarrhea) while the prednisone taper is on-going. These patients should have received initial high-dose corticosteroid therapy (˃ 1 mg/kg/day prednisone or equivalent) with resulting clinical resolution of diarrhea (NCI CTCAE v 5.0 grade ˂ 1 diarrhea) for at least 24 hours before relapse
• Hemoglobin ≥ 9.0 g/dL (within 14 days prior to study enrollment)
• Absolute neutrophil count (ANC) ≥ 1,000/mcL (within 14 days prior to study enrollment)
• Platelets ≥ 75,000/mcL (within 14 days prior to study enrollment)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to study enrollment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN (within 14 days prior to study enrollment) * If AST/ALT and serum creatinine elevation are suspected to be immune-mediated adverse events (irAEs), patients are eligible as long as the irAE are controlled (i.e. not getting worse at the time of enrollment)
• Measured creatinine clearance > 40 mL/min or estimated glomerular filtration rate (GFR) > 40 mL/min (within 14 days prior to study enrollment) * If AST/ALT and serum creatinine elevation are suspected to be irAEs, patients are eligible as long as the irAE are controlled (i.e. not getting worse at the time of enrollment)
• Well controlled diabetes with hemoglobin A1c (HbA1c) of < 8 with in 6 months of screening
• Euvolemic on physical examination
• Stable vital signs at screening and enrollment that includes * Body temperature 95.8 to 99.9°F * Heart rate between 60-100/min * Blood pressure 90-140/60-90 mm of Hg
• Must be on standard antidiarrheal supportive care for at least 1 day prior to starting RMT. The regimen consists of: loperamide 2-4 mg every 6 hours (up to 16 mg /day) and/or diphenoxylate 5 mg/ atropine sulfate 0.05 mg (2 tabs or 10 ml) up to 4 times daily as needed. This will continue until resolution of diarrhea to NCI CTCAE v 5.0 grade ≤ 1
• Age 18 years of age or older at the time of consent
• Body weight of > 30 kg
• Expected survival for at least 6 months in the opinion of the enrolling investigator as documented in the medical record
• Women of childbearing potential and men with partners of child-bearing potential must agree to use a highly effective form of contraception during study treatment and for at least 90 days after the last dose of study treatment. Persons are considered to be of childbearing potential unless one of the following applies: * Is postmenopausal, defined as no menses for at least 12 months without an alternative medical cause * Considered permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy Examples of highly effective birth control methods include but are not limited to the following: * Double-barrier contraception by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam * Oral contraceptive pills * Injectable contraception (i.e., Depo Provera) * Intrauterine device (IUD) * Transdermal contraceptive patch * Vaginal contraceptive ring * Contraceptive implants * Abstinence ** Note: Rhythm method alone is not considered an adequate method of contraception
• Voluntary written consent prior to the performance of any research related activity

Exclusion Criteria

• Diagnosis of concomitant infectious colitis based on standard stool screening including stool microscopy for ova and parasites, stool polymerase chain reaction (PCR) for Clostridioides difficile, and locally available common enteric bacterial pathogen and viral panel by PCR
• Last cytotoxic chemotherapy or targeted therapy less than 3 week prior to screening
• Patients anticipated to require cytotoxic chemotherapy or targeted therapy through the end of treatment (EOT) period (30 days following first dose of RMT)
• Known current pregnancy or breastfeeding
• Receiving another investigational agent or has received an investigational agent within 60 days of study enrollment
• Any other uncontrolled grade ≥ 3 infection at the time of enrollment (concomitant systemic antibiotics for non-gastrointestinal [GI] infections are allowed)
• Previous documented history of chronic diarrhea from non-IMDC causes (For example: inflammatory bowel disease [e.g., Crohn’s disease, ulcerative colitis])
• Known dysphagia or inability to swallow study capsules (CTCAE v5 dysphagia grade ≥ 2 - symptomatic and altered eating/swallowing)
• Known risk of aspiration based on history or current complaints
• Has a known sensitivity to any component of therapeutic agents used in this study
• On intravenous biologic agents for other baseline autoimmune conditions
• Other concomitant uncontrolled irAE’s at the time of enrollment which would require systemic corticosteroids or biologic immunomodulatory agents
• On chronic systemic antibiotic therapy (antibiotics for ≥ 60 consecutive days within 12 weeks of enrollment)
• Receipt of over-the-counter probiotics in the last 4 weeks
• Receipt of live attenuated vaccination within 30 days of receiving RMT. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chickenpox (except shingrix), yellow fever, nasal seasonal flu, nasal swine influenza A (H1N1) flu, rabies, Bacillus Calmette-Guerin (BCG), and typhoid – coronavirus disease 2019 (COVID-19) vaccination is permitted
• Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent