A Pilot Study Testing the Safety and Feasibility of Restorative Microbiota Therapy (RMT) in Patients With Refractory Immune-checkpoint Inhibitor-related Colitis

Study Overview
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Brief Summary
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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.

Official Title
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A Pilot Study Testing the Safety and Feasibility of Restorative Microbiota Therapy (RMT) in Patients With Refractory Immune-checkpoint Inhibitor-related Colitis

Conditions
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Immune-related Colitis, Colitis

Intervention / Treatment
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* Drug: RMT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced or metastatic solid tumors who have received at least two doses of ICI (PD-1/PD-L1 with or without CTLA-4 inhibitor) within 6 months of the onset of steroid-refractory IMDC symptoms. The ICI may be used as a single agent, or combination or ICI in combination with other cytotoxic chemotherapy or targeted therapy for curative or palliative intent treatment. Meet one of the criteria for steroid refractory IMDC defined as: Persistent symptoms (NCI CTCAE v 5.0 Grade ≥ 2 diarrhea) 72 hours after the patient received the high-dose corticosteroid therapy (>1 mg/kg/d prednisone or equivalent) or Symptoms relapsed (NCI CTCAE v 5.0 Grade ≥ 2 diarrhea) upon tapering to 1mg/kg/d or more of prednisone or equivalent or Persistent symptoms (ongoing Grade ≥ 2 diarrhea per CTCAE v5.0.) following use of a one or more biologic agent (i.e. either a TNFα inhibitor or an anti-integrin) in addition to steroids. Adequate organ function within 14 days of study enrollment defined as: Hematology: Hemoglobin ≥9.0 g/dL, absolute neutrophil count (ANC) ≥1,000/mcL, platelets ≥75,000/mcL, Hepatic function: Total bilirubin ≤ 1.5x upper limit of normal (ULN), AST (SGOT) and ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤5x ULN) Renal function: measured creatinine clearance &gt;40 mL/min or estimated glomerular filtration rate (eGFR) &gt; 40 mL/min 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) Able to provide written consent prior to any research related activities Exclusion Criteria: Known current pregnancy or breastfeeding Diagnosis of concomitant infectious colitis (e.g. C. difficile or other bacterial or viral source or parasitic), unless the patient has finished an appropriate length of treatment with antibiotics as indicated for each diagnosis at the time of enrollment 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-GI infections are allowed) Active documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) Previous documented history of chronic diarrhea from non-IMDC causes CTCAE v 5 Dysphagia Grade 2 (symptomatic and altered eating/swallowing) or greater Known risk of aspiration based on history or current complaints

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RMT group<br>16 patients will be randomized to Oral restorative microbiota therapy (RMT). Consenting eligible participants receive a loading dose of RMT capsules. | Drug: RMT<br>* A 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.<br>|
| Placebo Comparator: active placebo<br>participants in the placebo arm will receive an identical looking placebo capsules | Drug: Placebo<br>* Participants 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurrence of adverse events | assessed by the occurrence of adverse events Grade ≥3 per NCI's Common Terminology Criteria for Adverse Events (CTCAE v5.0). | 6 months after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary efficacy of oral RMT in inducing clinical remission- Day 10 | diarrhea of Grade <= 1 of refractory IMDC at Day 10 (+-3) from the 1st dose of RMT | Day 10 | 
| Primary efficacy of oral RMT in inducing clinical remission- Day 30 | diarrhea of Grade <= 1 of refractory IMDC at Day 30 (+-5) from the 1st dose of RMT | Day 10 | 
| Days for clinical remission | Efficacy of RMT to induce a clinical remission of refractory IMDC as measured by time in days necessary to achieve a diarrhea of Grade <=1 | Day 180 |