Fecal Transplant +/- Gut Decontamination in Preventing Acute Graft Versus Host Disease in Patients Given Broad-Spectrum Antibiotics

Randomized Phase II Trial of Total Gut Decontamination Followed by Fecal Microbiota Transplant (FMT), FMT-Alone or Standard of Care for Reduction in Acute Graft-Versus-Host Disease of the Gastrointestinal Tract in Patients Given Broad-Spectrum Antibiotics

This phase II trial studies how well a fecal microbiota transplant with or without total gut decontamination works in preventing graft versus host disease in patients exposed to broad-spectrum antibiotics. Fecal microbiota transplantation is the administration by enema of fecal matter (stool) that includes helpful bacteria from a normal, healthy donor. Total gut decontamination uses antibiotics to remove/reduce the amount of bacteria in the digestive system. It is not yet known if a fecal microbiota transplant with or without total gut decontamination works better in preventing graft versus host disease compared to standard immunosuppressive therapies (therapies that lower the normal function of the immune system).

Study Overview

• Status: Withdrawn
• Conditions: Graft-versus-host Disease Prevention
• Intervention / Treatment: Procedure: Fecal Microbiota Transplantation; Drug: Nystatin; Drug: Piperacillin-Tazobactam; Other: Best Practice

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients who develop acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract by day 100 post-transplant for patients randomized to the standard of care, total gut decontamination (TGD) followed by fecal microbiota transplant (fecal microbiota transplantation [FMT]) and FMT alone arms.

SECONDARY OBJECTIVES:

I. Overall maximum stage of lower GI tract GVHD by day 100 post-transplant. II. Cumulative incidence of acute GVHD grade II-IV and maximum grade through 6 months.

III. Time to onset of acute GVHD and acute GI GVHD. IV. Incidence of adverse events and serious adverse events. V. Incidence of bacterial blood stream infections through 6 months. VI. Hematologic recovery (neutrophils and platelets). VII. Characterization of the intestinal microbiota at enrollment, pre-FMT / time of engraftment, 2 month post-FMT/ engraftment, onset of gastrointestinal tract (GIT) GVHD, and at study completion (6 months).

VIII. Relapse-free survival at 6 months post-randomization. IX. Non-relapse mortality at 6 months post-randomization. X. Overall survival (OS) at 6 months post-randomization.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A (TGD + FMT): Patients receive piperacillin-tazobactam orally (PO) three times daily (TID) and nystatin PO four times daily (QID) until FMT. Patients undergo stem cell transplantation on day 0, then undergo FMT via enema over 5-10 minutes within 3 weeks after transplantation.

ARM B (FMT): Patients undergo stem cell transplantation on day 0, then undergo FMT via enema over 5-10 minutes within 3 weeks after transplantation.

ARM C (STANDARD THERAPY): Patients receive standard of care.

After completion of study treatment, patients are followed up at 100 days and 6 months.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who are day -10 pre- to day +30 post-allogeneic hematopoietic cell transplant (AHCT) from any donor or graft source and for any conditioning regimen
• Patients who have received treatment with meropenem or piperacillin-tazobactam (pip-tazo) intravenously (IV) (of at least 24 hours duration) in past 7 days
• Controlled infection defined as hemodynamically stable and not requiring supplemental oxygen of more than 2 liters via nasal cannula
• Patients who are able to take oral medications in suspension form
• Patients who are able to provide informed consent (IC) and comply with all study visits and procedures

Exclusion Criteria:

• Patients who are anticipated to require continued broad spectrum antibiotics with meropenem or pip-tazo IV for > 96 hours post-engraftment such as for known, documented infections necessitating prolonged treatment
• Patients with a prior documented infection with mycormycetes
• Patients who are greater than 2 days from time of neutrophil engraftment post AHCT
• Patients with active enteric infections
• Patients with acute GVHD >= grade II
• Patients unwilling or unable to undergo the FMT via retention enema procedure
• Patients who have received treatment with an investigational agent within 2 weeks of enrollment
• Patients unable to tolerate oral decontamination regimen of pip-tazo and nystatin due to prior allergy or intolerance of these medications
• Patients with any medical or psychological condition that, in the opinion of the investigator, might interfere with the subject's participation in the trial, pose any additional risk for the subject, or confound the assessments of the subject

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (TGD + FMT); Patients receive piperacillin-tazobactam PO TID and nystatin QID. Patients undergo stem cell transplantation on day 0, then undergo FMT via enema over 5-10 minutes within 3 weeks after transplantation.	Procedure: Fecal Microbiota Transplantation; Undergo FMT; Other Names: Fecal Material Transplantation; Fecal Transplantation; FMT; Poo Transplant; Poop Transplant; Stool Transplant; Drug: Nystatin; Given PO; Other Names: Mycostatin; Nystex; Drug: Piperacillin-Tazobactam; Given PO; Other Names: Zosyn; PIPER/TAZO; Piperacillin/Tazobactam
Experimental: Arm II (FMT); Patients undergo stem cell transplantation on day 0, then undergo FMT via enema over 5-10 minutes within 3 weeks after transplantation.	Procedure: Fecal Microbiota Transplantation; Undergo FMT; Other Names: Fecal Material Transplantation; Fecal Transplantation; FMT; Poo Transplant; Poop Transplant; Stool Transplant
Active Comparator: Arm III (standard therapy); Patients receive standard of care.	Other: Best Practice; Given standard of care; Other Names: standard of care; standard therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of acute gastrointestinal (GI) graft versus host disease (GVHD)	Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	Within 100 days from time of transplant
Relapse-free survival	Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or myelodysplastic syndrome (MDS) inconstant with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The distribution of time-to-event endpoints, as well as the median and 90% confidence interval, will be estimated using the Kaplan-Meier method.	At 6 months post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiome diversity	Will be measured using the inverse Simpson index. Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	At 2 weeks post fecal microbiota transplantation (FMT) (or engraftment for control arm)
Overall maximum stage of lower GI tract GVHD	Will be defined as the proportion of patients who do not develop GI GVHD within 100 days post-transplant and will be monitored simultaneously in cohorts of 5 patients separately in each arm using the approach of Thall, Simon, and Estey.	Within 100 days post-transplant
Cumulative incidence of acute GVHD grade II-IV and maximum grade	Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	Up to 6 months
Incidence of adverse and serious adverse events	Defined as the proportion of patients who develop blood stream infections caused by enteric bacteria within 60 days of FMT. Will be monitored simultaneously in cohorts of 5 patients separately in each arm using the approach of Thall, Simon, and Estey.	Within 60 days of FMT
Incidence of bacterial blood stream infections	Will identify those caused by a potential enteric pathogen. Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	Up to 6 months
Hematologic recovery (neutrophils and platelets)	Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	Up to 6 months
Characterization of the intestinal microbiota	Summary statistics, including mean, median, range, and standard deviation, will be provided for continuous variables. Frequency tables will be used to summarize categorical variables.	Baseline up to 6 months
Non-relapse mortality	Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS inconstant with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The distribution of time-to-event endpoints, as well as the median and 90% confidence interval, will be estimated using the Kaplan-Meier method.	At 6 months post-randomization
Overall survival	The distribution of time-to-event endpoints, as well as the median and 90% confidence interval, will be estimated using the Kaplan-Meier method.	At 6 months post-randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of T-cell subsets	Analysis of T-cell subsets (including specifically regulatory T-cells) will be performed by characterization of peripheral blood flow cytometry.	Up to 6 months post-enrollment
Analysis of serum/stool butyrate levels		Up to 6 months post-enrollment
Assessment of gut permeability	Will be performed via lactulose/ mannitol assay.	At time of discontinuation of antibiotics (engraftment)

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Amin M Alousi, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2020
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): March 4, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Membrane Transport Modulators; Antifungal Agents; beta-Lactamase Inhibitors; Ionophores; Piperacillin; Nystatin; Tazobactam; Piperacillin, Tazobactam Drug Combination
• Other Study ID Numbers: 2017-0466 (Other Identifier: M D Anderson Cancer Center); P30CA016672 (U.S. NIH Grant/Contract); NCI-2019-01045 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No