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

Phase 2

Not yet recruiting

• Conditions: Immune-related Colitis; Colitis
• Interventions: Drug: RMT; Drug: Placebo

• Registration Number: NCT05726396
• Lead Sponsor: University of Minnesota

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-02-04
• Study First Submitted QC: 2023-02-04
• Study First Posted: 2023-02-13
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-08
• Last Update Posted: 2025-07-11
• Study Start: 2025-08-13
• Primary Completion: 2026-02-01
• Study Completion: 2026-02-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• 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

• Meet one of the criteria for steroid refractory IMDC defined as:

  1. 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
  2. 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 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
  3. 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
  4. 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

• Adequate organ function within 14 days prior to study enrollment defined as:

  1. Hematology: Hemoglobin ≥9.0 g/dL, absolute neutrophil count (ANC) ≥1,000/mcL, platelets ≥75,000/mcL,
  2. 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)
  3. Renal function: measured creatinine clearance >40 mL/min or estimated glomerular filtration rate (GFR) >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)

• Well controlled diabetes with HbA1c of <8 with in 6 months of screening

• Euvolemic on physical examination

• Stable vital signs at screening and enrollment that includes

  1. Body temperature 95.8 to 99.9°F
  2. Heart rate between 60-100/min
  3. 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

• 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 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-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 H1N1 flu, rabies, BCG, and typhoid - 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RMT group	RMT	16 patients will be randomized to Oral restorative microbiota therapy (RMT). Consenting eligible participants receive a loading dose of RMT capsules.
active placebo	Placebo	participants in the placebo arm will receive an identical looking placebo capsules

Primary Outcome Measures

Name	Time	Method
Feasibility and safety of RMT	6 months after baseline	Feasibility and safety of RMT as assessed by the occurrence of adverse events

Secondary Outcome Measures

Name	Time	Method
Clinical remission by Day 10	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	Day 30	Incidence of clinical remission of refractory IMDC at Day 30 following first dose of RMT
Time for clinical remission	Day 180	Days to induce a clinical remission of refractory IMDC necessary to achieve a diarrhea of Grade \<= 1

Trial Locations

Locations (1)

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States