Oral Supplementation of 2'-Fucosyllactose in Allogeneic Bone Marrow Transplant Recipients

Study Overview
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Brief Summary
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High dose chemotherapy and radiation used as preparative regimens in patients undergoing an allogeneic hematopoietic stem cell transplant (HSCT) disrupts intestinal homeostasis by damaging the intestinal epithelium and altering the intestinal microbiome. The investigators hypothesize that 2'-fucosyllactose (2FL) supplementation will be safe and tolerable and result in an increase in the relative abundance of intestinal Bifidobacteria. The investigators also hypothesize that 2FL supplementation will lead to reduction of Firmicutes and/or Proteobacteria, and improved intestinal homeostasis at day+30 as measured by lower pro-inflammatory cytokines, reduced levels of T-cell activation, lower markers of intestinal injury (fecal human DNA and plasma reg-3-alpha), increased fecal butyrate levels and ultimately lower incidence of acute GVHD and BSI at day+100. Phase II: The investigators hypothesize that 2FL supplementation will be safe and tolerable and result in an increase in the relative abundance of fecal short chain fatty acids such as butyrate, acetate and propionate at day+7 compared to baseline values.

Detailed Description
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This phase I/IIa study is a single center prospective study at Cincinnati Children's Hospital Medical Center (CCHMC). This study will assess the safety and tolerability of various doses of 2FL. Eligible patients will be allocated to the following arms as determined by age at enrollment: Arm 1: 0-5 years; Arm 2: 5.1-10 years; Arm 3: >10 years The investigators will first enroll 5 patients of ages ≥10 years undergoing allogeneic HSCT. 2'-FL will be administered to these patients from day-7 until day+30 after HSCT at the starting dose for the ≥10 years age group. Once safety is determined the investigators will then enroll an additional 5 patients of ages 5-10 years and 5 patients of ages 0-5 years and administer 2'FL at starting doses according to their age group to children from day-7 to day+30 after HSCT. Enrollment in the 2 defined age groups (5-10 years and 0-5 years) will occur independent of each other/in parallel to establish safety. Once safety is established in these patients the investigators will proceed with the 3x3 study design dose finding portion of our study Three patients will be enrolled in each arm at the starting dose level. Investigators will perform a dose escalation or de-escalation based on rates of dose limiting toxicities. Phase II: Initial 15 patients to establish safety as per the FDA have been enrolled. An additional 10 patients were enrolled and interim analyses demonstrating safety, lack of any dose limiting toxicities and a positive signal of increase in fecal acetate and propionate at day+7 compared to baseline values) were performed. The investigators will enroll approximately 45 additional patients to test efficacy of 2FL supplementation in children and young adult allogeneic HSCT patients with a goal to reduce intestinal inflammation and improve post HSCT outcomes such as acute GVHD and bloodstream infections.

Official Title
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Oral Supplementation of 2'-Fucosyllactose in Allogeneic Bone Marrow Transplant Recipients to Maintain Intestinal Homeostasis

Conditions
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Hematopoietic Stem Cell Transplant

Intervention / Treatment
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* Drug: 2'-fucosyllactose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be scheduled for allogeneic stem cell transplant All ages and underlying diagnoses, preparative regimens, stem cell sources and acute GVHD prophylaxes Exclusion Criteria: Unable to take anything orally or enterally (i.e. intestinal failure) Actively breastfeeding infants Recent (within the week prior to enrollment) GI infection Patients receiving anti-diarrheal medications such as loperamide Patients who have received probiotics or prebiotics during the previous month Patients who have had any type of gut damage within the past 3 months such as previous bowel perforations, previous episode of Grade 4 neutropenic colitis or typhlitis Patients with inflammatory bowel disease, short bowel syndrome, and patients with a history of bowel resections

Ages Eligible for Study
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Minimum Age: 0 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be allocated into the following arms as determined by age at enrollment. Arm 1: 0-5 years; Arm 2: 5.1-10 years; Arm 3: >10 years
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2'-fucosyllactose for ages 0-5 years<br>Dose for ages 0-5 years: 2.5 g/day; | Drug: 2'-fucosyllactose<br>* 2FL powder will be provided to participants randomized to receive 2FL in packets. They will be instructed to drink this daily by adding the required amount to food or drink. It may also be mixed in standard feeds or mixed with water and administered by enteral tube, whenever applicable.<br>* Other names: 2FL supplementation;|
| Experimental: 2'-fucosyllactose for ages 5.1-10 years<br>Dose for ages 5.1-10 years: 5 g/day; | Drug: 2'-fucosyllactose<br>* 2FL powder will be provided to participants randomized to receive 2FL in packets. They will be instructed to drink this daily by adding the required amount to food or drink. It may also be mixed in standard feeds or mixed with water and administered by enteral tube, whenever applicable.<br>* Other names: 2FL supplementation;|
| Experimental: 2'-fucosyllactose for ages >10 years<br>Dose for ages >10 years: 10 g/day; | Drug: 2'-fucosyllactose<br>* 2FL powder will be provided to participants randomized to receive 2FL in packets. They will be instructed to drink this daily by adding the required amount to food or drink. It may also be mixed in standard feeds or mixed with water and administered by enteral tube, whenever applicable.<br>* Other names: 2FL supplementation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of bloodstream infections | Number of bloodstream infections in patients on 2FL | Day+100 after transplant | 
| Number of patients able to take 2FL | 6 of 10 patients receiving 2FL able to take 80% of their planned doses | 1 week prior to start of chemotherapy until day+30 after transplant | 
| Incidence of mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI) | Incidence of MBI-LCBI in patients enrolled in phase II of the study | Day+ 100 after transplant | 
| Incidence of graft versus host disease (GVHD) | Incidence of GVHD in patients enrolled in phase II of the study | Day+ 100 after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative abundance of fecal Bifidobacteria at day+30 compared to baseline by >/=10% | Change in relative abundance of fecal Bifidobacteria at day+30 compared to baseline by >/=10% | Day+30 after transplant | 
| Relative abundance of fecal Firmicutes and Proteobacteria at day+30 compared to baseline for patients on 2FL | Change in relative abundance of fecal Firmicutes and Proteobacteria at day+30 compared to baseline for patients on 2FL | Day+30 after transplant | 
| Incidence of acute GVHD | Incidence of acute GVHD in patients on 2FL | Day+100 after transplant | 
| Incidence of bloodstream infections | Incidence of bloodstream infections in patients on 2FL | Day+100 after transplant | 
| Increase in fecal butyrate/acetate/propionate levels | Increase in fecal butyrate/acetate/propionate levels from baseline at day+ 7 in patients enrolled in phase II of the study | Day+ 7 after transplant |