Immune-related colitis from immune checkpoint inhibitors (ICI) is a common adverse effect causing significant morbidity and impairment of quality of life (QoL). Steroids are the first line of treatment for severe ICI induced Immune- mediated diarrhea and colitis (IMDC). If there is no improvement in 48 to 72 hours, other immunosuppressive agents (infliximab, vedolizumab) are recommended. However, efficacy data supporting the use of immunosuppressives for steroid refractory IMDC is limited by case reports/series. Clinical trials focusing on steroid-refractory colitis are sparse. Novel treatments for IMDC outside of blanket immunosuppression are needed. There is robust evidence to suggest that gut microbial diversity and composition is associated with both ICI efficacy and toxicity. Preliminary studies have shown that pathophysiology of immune mediated colitis may be related to loss of gut microbial diversity. Recently, multiple case series have shown the utility of fecal microbiota transplant for treatment of refractory IMDC providing the proof of concept. This is a pilot randomized placebo controlled study to assess the safety and feasibility of oral restorative microbiota therapy (RMT) in patients with steroid- refractory IMDC.
Localized, locally advanced or metastatic solid tumors who have received at least two doses of 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
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
Diagnosis of concomitant infectious colitis based on standard stool screening including stool microscopy for ova and parasites, stool 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.
Parallel
RMT
DrugA single loading dose of RMT capsules containing \~5 x 10 11 bacteria on day 1 followed by 2 x 10 11 bacteria daily for 6 days. The RMT capsule preparation (\~2-5 capsules, size 00) is self-administered on an empty stomach with at least one glass of water. Clear liquids are allowed, and food can be resumed 2 hours after administration.
Placebo
DrugParticipants will receive an identical looking placebo capsules daily for 7 days (i.e 5 placebo capsules on day 1), followed by 2 placebo capsules daily from Day 2-7. The placebo capsule preparation is self-administered on an empty stomach with at least one glass of water. Clear liquids are allowed, and food can be resumed 2 hours after administration.
Feasibility and safety of RMT
Feasibility and safety of RMT as assessed by the occurrence of adverse events
Clinical remission by Day 10
Proportion of patients who experience diarrhea resolution to Grade \<= 1 of refractory IMDC at Day 10 from 1st dose of RMT
Clinical remission by Day 30
Incidence of clinical remission of refractory IMDC at Day 30 following first dose of RMT
Time for clinical remission
Days to induce a clinical remission of refractory IMDC necessary to achieve a diarrhea of Grade \<= 1
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