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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Graft-versus-host Disease Prevention

Intervention / Treatment
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* Other: Best Practice
* Procedure: Fecal Microbiota Transplantation
* Drug: Nystatin
* Drug: Piperacillin-Tazobactam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (TGD + FMT)<br>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<br>* Undergo FMT<br>* Other names: Stool Transplant;Drug: Nystatin<br>* Given PO<br>* Other names: Nystex;Drug: Piperacillin-Tazobactam<br>* Given PO<br>* Other names: Zosyn;|
| Experimental: Arm II (FMT)<br>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<br>* Undergo FMT<br>* Other names: Stool Transplant;|
| Active Comparator: Arm III (standard therapy)<br>Patients receive standard of care. | Other: Best Practice<br>* Given standard of care<br>* Other names: standard therapy;|

What is the study measuring?
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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 |