Clinical trial NCT04373057: Prebiotic Galacto-oligosaccharide and Acute GVHD
Official title: A Phase I/II Trial of the Prebiotic Galacto-oligosaccharide to Prevent Acute GVHD
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute GVHD
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2020-05-04
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: provisional Maximum Tolerated Dose (pMTD) of GOS
timeFrame: 30 days
measure: Incidence of Grade II-IV acute GVHD at Day 100
timeFrame: 100 days
Secondary outcomes:
measure: Incidence of acute GI toxicities through Day 30
timeFrame: 30 days
measure: Incidences of Acute GI toxicities as measured by self-reported evaluation through Day 30
timeFrame: 30 days
measure: Incidence of chronic GVHD at Day 365 and Day 730
timeFrame: Day 365 and day 730
measure: Health care utilization through Day 100, through Day 365, and through Day 730
timeFrame: Day 100, Day 365, and Day 730
measure: Overall survival (OS) at Day 365 and Day 730
timeFrame: Day 365 and Day 730
measure: Relapse-free survival (RFS) at Day 365 and Day 730
timeFrame: Day 365 and Day 730
measure: Total parenteral nutrition (TPN) use through Day 30 and Day 100
timeFrame: Day 30 and Day 100
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke
state: North Carolina
Study officials:
affiliation: Duke Health
name: Mitchell Horwitz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke Health
name: Anthony Sung, MD
role: PRINCIPAL_INVESTIGATOR
References: