Lactobacillus Plantarum in Preventing Acute Graft Versus Host Disease in Children Undergoing Donor Stem Cell Transplant

Lymphoma Clinical Trial

Official title:

The Effectiveness of Lactobacillus Plantarum (LBP, IND# 17339) in Preventing Acute Graft-Versus-Host Disease (GvHD) in Children Undergoing Alternative Hematopoietic Progenitor Cell Transplantation (HCT)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03057054
• Other study ID #: ACCL1633
• Secondary ID: NCI-2017-00208AC
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 30, 2018
• Est. completion date: June 30, 2024

Study information

• Verified date: October 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies how well Lactobacillus plantarum works in preventing acute graft versus host disease in children undergoing donor stem cell transplant. Lactobacillus plantarum may help prevent the development of gastrointestinal graft versus host disease in children, adolescents, and young adults undergoing donor stem cell transplant.

Description:

PRIMARY OBJECTIVE:

I. To determine efficacy of orally-administered Lactobacillus plantarum (LBP) in preventing the development of gastrointestinal (GI) acute graft versus host disease (aGvHD) in children and adolescents undergoing alternative donor allogeneic hematopoietic cell transplantation (alloHCT).

EXPLORATORY OBJECTIVES:

I. To determine whether orally-administered LBP decreases the incidence of grade II-IV aGvHD following alternative donor alloHCT.

II. To determine whether LBP administration maintains intestinal integrity as measured by mean serum citrulline levels and reduction in mucosal barrier injury (MBI) bacteremia.

III. To measure the effects of LBP on the intestinal flora phylogenetic composition during and after alternative donor alloHCT using 16S ribosomal ribonucleic acid (rRNA) gene deep sequencing.

IV. To measure effects of LBP on intestinal flora function during and after alternative donor alloHCT using metagenomic and metabolite profiling.

V. To measure proposed immunomodulatory effects of LBP in mean serum levels of alloreactive-induced inflammatory cytokines (IL-2, IL-6, IL-12p70, IFN gamma, TNF alpha, etc) in patients receiving LBP compared to placebo.

VI. To determine whether LBP administration reduces the incidence of Clostridium difficile-associated diarrhea in alternative donor HCT patients.

VII. To determine whether LBP administration reduces hospital days within the first 120 days post hematopoietic cell transplant (HCT).

VIII. To define the safety of orally administered LBP strains 299 and 299v in alternative donor HCT patients as measured by incidence of Lactobacillus plantarum bacteremia.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive Lactobacillus plantarum strains 299 and 299v orally (PO) or through nasojejunal (NJ), nasogastric (NG) or gastronomy (G) tube once daily (QD) on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

ARM II: Patients receive placebo PO or through NJ, NG or G tube QD on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

After completion of study treatment, patients are followed up for 120 days from alloHCT.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 173
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 25 Years

Eligibility

Inclusion Criteria:

• All clinical and laboratory studies, if applicable, must be obtained within 21 days prior to start of protocol therapy (repeat if necessary); protocol therapy must begin within 6 months of study enrollment

• Patient must have a diagnosis that is managed with an alternative donor allogeneic hematopoietic cell transplant

• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 70; patients who are unable to walk because of a chronic underlying condition (such as paralysis), but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score

• Hematopoietic cell transplant (HCT)

• Patient must be receiving cells from alternative donor defined as one of the following:

• Unrelated donor with a complete human leukocyte antigen (HLA) match or a 1 or 2 HLA mismatch, considering only HLA-A, HLA-B, HLA-C, and HLA-DRB1

• Related donor with a 1 or more HLA mismatch (including haplo-identical)

• Note: History of HCT or other cellular therapy (e.g. chimeric antigen receptor [CAR]-T cells, donor lymphocyte infusions) is permitted

Exclusion Criteria:

• Patient plans on receiving stem cells from a matched (8/8) related donor

• Patient has used a probiotic dietary supplement within the previous 30 days of enrollment; (consumption of yogurt products is allowed)

• Patient has a history of severe GI tract insult including but not limited to previous bowel perforation, grade 4 neutropenic colitis or typhlitis, inflammatory bowel syndrome, short small bowel syndrome (Crohn's disease, ulcerative colitis), history of gastrointestinal GVHD, or history of bowel resection

• Patient has a medical, psychiatric or social issue that would compromise patient safety or compliance with protocol therapy, or interfere with consent, study participation, follow up, or interpretation of study results

• Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to enrollment

• Patient has diarrhea at the time of enrollment which is Clostridium difficile toxin positive

• Patient is receiving antibiotic therapy for an active bacterial infection

• Patient is allergic to all third or fourth generation cephalosporins, carbapenems, and all aminoglycosides, which are used to empirically treat LBP bacteremia

Related Conditions & MeSH terms

• Graft vs Host Disease
• Hematopoietic and Lymphoid System Neoplasm
• Leukemia
• Lymphoma

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo alloHCT

Biological:
• Lactobacillus plantarum strain 299
Given PO or via NJ, NG or G tube
• Lactobacillus plantarum strain 299v
Given PO or via NJ, NG or G tube

Other:
• Placebo Administration
Given PO or via NJ, NG or G tube

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Medical City Dallas Hospital	Dallas	Texas
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	University of Rochester	Rochester	New York
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of Grade II-IV Overall Graft Versus Host Disease	A similar analysis approach will be used as described for the primary outcome measure but using the dichotomous cumulative incidence of grade II-IV acute graft versus host disease as the endpoint measure.	Up to 120 days post stem cell infusion
Other	Incidence of Blood Stream Infection	The risk of mucosal barrier blood stream infections will be compared between two groups.	Up to 120 days post stem cell infusion
Other	Incidence of Clostridium Difficile (C. Diff)-Associated Diarrhea	Proportion of C. diff-associated diarrhea during the study period will be compared between arms.	Up to 120 days post stem cell infusion
Other	Serum Levels of Citrulline	The change in citrulline levels from baseline to each of the time points (days 7, 14, 28, 56, and 120 post-infusion) will be summarized and described by arm.	Up to 120 days post stem cell infusion
Other	Bacterial Genes and Pathways, and Bacterial Metabolites (Blood/Stool Measures of Intestinal Flora - Function and Phylogenetic Composition)	LBP introduction on the intestinal flora via LBP administration will be compared with bacterial genes and pathways, and bacterial metabolites via correlation analyses. Also, dDescriptive analysis will be used to examine the association between the graft versus host disease outcomes (GI aGvHD and overall GvHD) and bacterial genes, pathways, and metabolites.	Up to 120 days post stem cell infusion
Other	Blood/Stool Measures of Intestinal Flora Assessed Using Sequencing	The association between Lactobacillus plantarum administration and bacterial genes and pathways, and bacterial metabolites will be evaluated.	Up to 120 days post stem cell infusion
Other	Levels of Pro-inflammatory Cytokines	The effects of Lactobacillus plantarum on pro-inflammatory (LBP) cytokines in allogeneic hematopoietic cell transplantation recipients will be examined by comparing levels across arms.	Up to 120 days post stem cell infusion
Other	Hospital Days	Total hospital days over the study period is calculated as the duration between the date of admission for conditional therapy and the date of discharge (or the study end date). Hospital days will be compared between arms.	Up to 120 days post stem cell infusion
Other	Incidence of Lactobacillus Plantarum Bacteremia	Patients who have at least one incidence (positive) of lactobacillus plantarum during any reporting period is considered evaluable for this aim. The proportion of patients experiencing lactobacillus plantarum bacteremia during the study period will be compared between arms.	Up to 120 days post stem cell infusion
Primary	Proportion of Participants With Stage 1-4 Gastrointestinal (GI) Acute Graft Versus Host Disease (aGVHD)	The proportion of eligible patients having stage 1-4 GI aGvHD occur from Day 0 through Day 120 will be compared between the two arms.	Up to 120 days post stem cell infusion