Prebiotic Galacto-oligosaccharide and Acute GVHD

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the carbohydrate prebiotic (dietary supplement) known as galacto-oligosaccharide (GOS) can modulate the microbiome (the bacteria in the gut) and help prevent graft-versus host disease (GVHD) after allogeneic stem cell transplant. The study has two two parts. In phase 1, the best dose of GOS will be evaluated. In phase 2, using the best dose of GOS, participants will be randomized to receive GOS or a placebo (maltodextrin, a common food additive that is not known to affect the microbiome) so that the effect of GOS can be determined.

Detailed Description
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Humans carry on the order of 100 trillion microbial cells (the microbiota),which play a major role in normal health as well as disease pathogenesis. In the gut, the microbiota interact with the intestinal epithelium and immune system to regulate inflammation and metabolism. The impact of the microbiota on GVHD and other clinical outcomes may be mediated by bacterial metabolites such as short chain fatty acid (SCFAs). In particular, the SCFA butyrate has been shown to be a preferred fuel source of human colonic epithelial cells and essential for normal differentiation of regulatory immune cells in the intestine, which in turn may decrease GVHD. This is supported by murine studies, in which manipulating the gut microbiota to increase microbial SCFA production or by direct administration (oral gavage) of butyrate has been shown to improve HCT outcomes, including protection from GVHD Manipulating the gut microbiota in HCT to decrease the risk of GVHD could potentially be done using several methods, namely prebiotics (dietary carbohydrates or fibers), probiotics (live bacteria), and fecal transplantation. In contrast to live bacteria, prebiotics are dietary carbohydrates classified as nutritional supplements that can sustain gut bacteria, regulate gastrointestinal transit time, and foster cooperative metabolic networks between enteric microbes. Because prebiotics encourage the growth of existing bacteria rather than introducing new organisms, they may be safer. Moreover, bacterial fermentation of prebiotics may yield SCFA. The purpose of this study is to determine whether the carbohydrate prebiotic (dietary supplement) known as galacto-oligosaccharide (GOS) can modulate the microbiome (the bacteria in the gut) and help prevent graft-versus host disease (GVHD) after allogeneic stem cell transplant. The study has two two parts. In phase 1, three dose levels 0.75g/day (25% maximum dose, D1), 1.5g/day (50% maximum dose D2), and 2.9g/day (maximum dose, D3) will be evaluated to find out the provisional maximum tolerated dose (pMTD) of GOS to be used in phase 2. In phase 2, using pMTD of GOS, participants will be randomized to receive GOS or a placebo (maltodextrin, a common food additive that is not known to affect the microbiome) so that the effect of GOS can be determined. Note that if the pMTD is D3, there will be a D1 and D2 lead-in period similar to the Phase 1 study however if the pMTD is D2, there will only be a lead-in with D1 and if pMTD is D1, there will only be one dose with no lead-in. The study will generate important data on gut microbiota responses to help tailor or personalize future prebiotic therapies to patients and their microbiota.

Official Title
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A Phase I/II Trial of the Prebiotic Galacto-oligosaccharide to Prevent Acute GVHD

Conditions
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Acute GVHD

Intervention / Treatment
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* Dietary Supplement: Galacto-oligosaccharide
* Dietary Supplement: Maltodextrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Plan to undergo allogeneic HCT for any cancer or non-cancer illness Age 18-80 years Karnofsky Performance Status >70 Exclusion Criteria: Pregnant/lactating Malabsorption syndrome, short bowel or chologenic diarrhea At time of enrollment, Grade 2 or higher GI symptoms per NCI-CTCAE Active treatment with other prebiotics, probiotics, or herbal supplementation (ok if stops before enrollment) Active treatment with antibiotics (with the exception of prophylactic antibiotics) Concurrent enrollment on the Duke HCT Home Transplant study or another clinical trial targeting GVHD; patients who are enrolled in observational or non-pharmacologic intervention trials (for example, the Duke HCT Research-POP Pre and Peri-HCT Optimization Program aka R-POP) or pharmacologic or cellular therapy trials with other targets (for example, NK DLI) are NOT excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Galacto-oligosaccharide<br>Phase I: Subjects will receive GOS, at dose levels 0.75g, 1.5g, and 2.9 g/day administered once daily. GOS will be dosed per the following schedule using a modified 3+3 design: 0.75g x 4 days, followed by 1.5g x 4 days, followed by 2.9g for the duration of the study starting from about 30 days before transplant to about 4 weeks after transplant. Phase II: Subjects will receive GOS, at dose levels 0.25*MTD, 0.5*MTD, and MTD with MTD determined by the phase 1 of the study, once daily from about 30 days before transplant to about 4 weeks after transplant. | Dietary Supplement: Galacto-oligosaccharide<br>* GOS will be administered at determined dose levels per protocol once daily from about 30 days before transplant to about 4 weeks after transplant.<br>* Other names: Bimuno®, B-GOS;|
| Placebo Comparator: Maltodextrin<br>Phase II: Subjects will receive maltodextrin at comparable dose level as GOS (in Phase II) once daily from about 30 days before transplant to about 4 weeks after transplant. | Dietary Supplement: Maltodextrin<br>* Maltodextrin will be administered at comparable dose level as GOS (in Phase II) once daily from about 30 days before transplant to about 4 weeks after transplant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| provisional Maximum Tolerated Dose (pMTD) of GOS | GOS will be dosed as outlined using a modified 3+3 design: 0.75g x 4 days, followed by 1.5g x 4 days, followed by 2.9g for the duration of the study. If two or more subjects experience new grade 2 or 3 pre-HCT toxicities at a given dose level, that dose will be considered not tolerable and the previous dose pMTD. If two or more subjects experience new grade 2 or higher pre-HCT toxicities at the 0.75g/day dose, study may be paused to revisit the design. If one subject experiences new grade 2 or 3 pre-HCT toxicities at a given dose level, additional 3 subjects will be enrolled at this same dose schedule. If one or more of these additional subjects experience new grade 2 or 3 pre-HCT toxicities at that same or lower dose level, this dose level will be considered not tolerable and the previous dose the pMTD. If no subjects experience new grade 2 or 3 pre-HCT toxicities or only one of six subjects experience new grade 2 or 3 pre-HCT toxicities, 2.9g/day dose will be assumed to be the pMTD | 30 days | 
| Incidence of Grade II-IV acute GVHD at Day 100 | Acute GVHD Scoring will be done following BMT CTN, 2013 criteria. | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute GI toxicities through Day 30 | Acute GI toxicities include mucositis, nausea, vomiting, diarrhea, constipation, abdominal pain, and bloating through D30 as assessed by CTCAE v5. | 30 days | 
| Incidences of Acute GI toxicities as measured by self-reported evaluation through Day 30 | Acute GI toxicities as measured by self-reported (PRO-CTCAE) evaluation of decreased appetite, anxiety, sadness, fatigue, insomnia, general pain, shortness of breath, numbness and tingling, mouth sores, nausea, vomiting, diarrhea, constipation, abdominal pain, and bloating through D 30 (5 point ordinal scale per PRO-CTCAE) | 30 days | 
| Incidence of chronic GVHD at Day 365 and Day 730 | Chronic GVHD Scoring will be done following NIH Consensus Criteria | Day 365 and day 730 | 
| Health care utilization through Day 100, through Day 365, and through Day 730 | Data will be obtained through chart review at or after Day 100, Day 365, and Day730 (respectively), and will be reported as means/medians depending on the distribution of data (for example, mean/median health care utilization through Day 100) | Day 100, Day 365, and Day 730 | 
| Overall survival (OS) at Day 365 and Day 730 | Data will be obtained by chart review at or after D365 and D730 Data will be reported as a percentage (ie. 1-year and 2-year overall survival) for each arm | Day 365 and Day 730 | 
| Relapse-free survival (RFS) at Day 365 and Day 730 | Data will be obtained by chart review at or after Day 365 and Day 730 Data will be reported as a percentage (ie. 1-year and 2-year overall survival) for each arm | Day 365 and Day 730 | 
| Total parenteral nutrition (TPN) use through Day 30 and Day 100 | Data will be obtained as part of the GVHD Prophylaxis/medication assessments. Data will be reported as a percentage for each arm (at each of the time points) | Day 30 and Day 100 |