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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma; Leukemia; Hematopoietic and Lymphoid System Neoplasm
• Intervention / Treatment: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Biological: Lactobacillus plantarum strain 299; Biological: Lactobacillus plantarum strain 299v; Other: Placebo Administration

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 173
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Science Center - Gainesville
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Hawaii
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial
  • Texas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • San Antonio, Texas, United States, 78207
      • Children's Hospital of San Antonio
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital of South Texas
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (Lactobacillus plantarum, alloHCT); Patients receive Lactobacillus plantarum strains 299 and 299v 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.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo alloHCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic; Biological: Lactobacillus plantarum strain 299; Given PO or via NJ, NG or G tube; Other Names: DSM 6595; LACTOBACILLUS PLANTARUM 299; Biological: Lactobacillus plantarum strain 299v; Given PO or via NJ, NG or G tube; Other Names: Lp 299v; DSM 9843; LACTIPLANTIBACILLUS PLANTARUM 299V
Placebo Comparator: Arm II (placebo, alloHCT); 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.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo alloHCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic; Other: Placebo Administration; Given PO or via NJ, NG or G tube

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Michael L Nieder, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2018
• Primary Completion (Actual): June 30, 2022
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: February 15, 2017
• First Submitted That Met QC Criteria: February 15, 2017
• First Posted (Actual): February 17, 2017

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: October 26, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: ACCL1633 (Other Identifier: CTEP); UG1CA189955 (U.S. NIH Grant/Contract); NCI-2017-00208 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); COG-ACCL1633 (Other Identifier: DCP); R01CA201788 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No