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

• ClinicalTrials.gov Identifier: NCT03057054
• Recruitment Status: Recruiting
• First Posted: February 17, 2017
• Last Update Posted: November 14, 2019
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Malignant Neoplasm	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Biological: Lactobacillus plantarum strain 299; Biological: Lactobacillus plantarum strain 299v; Other: Placebo	Phase 3

Detailed Description:

PRIMARY OBJECTIVES:

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 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 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: The Effectiveness of Lactobacillus Plantarum (LBP) in Preventing Acute Graft-Versus-Host Disease (GvHD) in Children Undergoing Alternative Hematopoietic Progenitor Cell Transplantation (HCT)
• Actual Study Start Date: April 30, 2018
• Estimated Primary Completion Date: October 30, 2023
• Estimated Study Completion Date: October 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (Lactobacillus plantarum, alloHCT); Patients receive Lactobacillus plantarum strains 299 and 299v PO or through 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 Hematopoietic Cell Transplantation; allogeneic stem cell transplantation; HSC; HSCT; Biological: Lactobacillus plantarum strain 299; Given PO or via NG or G tube; Other Name: DSM 6595; Biological: Lactobacillus plantarum strain 299v; Given PO or via NG or G tube; Other Names: DSM 9843; Lp 299v
Placebo Comparator: Arm II (placebo, alloHCT); Patients receive placebo PO or through 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 Hematopoietic Cell Transplantation; allogeneic stem cell transplantation; HSC; HSCT; Other: Placebo; Given PO or via NG or G tube; Other Names: placebo therapy; PLCB; sham therapy

Outcome Measures

Primary Outcome Measures :

1. Incidence of stage 1-4 gastrointestinal (GI) acute graft versus host disease (aGVHD) [ Time Frame: Up to 120 days post stem cell infusion ]
   The proportion of eligible patients having stage 1-4 GI aGvHD incidence from Day 0 through Day 120 will be compared between the two arms.

Other Outcome Measures:

1. Incidence of grade II-IV overall graft versus host disease [ Time Frame: Up to 120 days post stem cell infusion ]
   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.
2. Incidence of blood stream infection [ Time Frame: Up to 120 days post stem cell infusion ]
   The incidence of mucosal barrier blood stream infections will be compared between two groups.
3. Incidence of Clostridium difficile-associated diarrhea [ Time Frame: Up to 120 days post stem cell infusion ]
   Proportion of C. diff during the study period will be compared between arms.
4. Plasma levels of citrulline [ Time Frame: Up to 120 days post stem cell infusion ]
   The citrulline levels at each of the time points will be summarized and described by arm.
5. Graft versus host disease biomarkers [ Time Frame: Up to 120 days post stem cell infusion ]
   Descriptive analysis will be used to examine the association between graft versus host disease outcomes and bacterial genes, pathways, and metabolites.
6. Blood/stool measures of intestinal flora assessed using sequencing [ Time Frame: Up to 120 days post stem cell infusion ]
   The association between Lactobacillus plantarum administration and bacterial genes and pathways, and bacterial metabolites will be evaluated.
7. Laboratory correlative measures for allogeneic-induced inflammation [ Time Frame: Up to 120 days post stem cell infusion ]
   The effects of Lactobacillus plantarum on pro-inflammatory (LBP) cytokines in allogeneic hematopoietic cell transplantation recipients will be examined.
8. Hospital days [ Time Frame: Up to 120 days post stem cell infusion ]
   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.
9. Incidence of Lactobacillus plantarum bacteremia [ Time Frame: Up to 120 days post stem cell infusion ]
   Patients who have at least one incidence (positive) of Lactobacillus plantarum during any reporting period is considered evaluable for this aim. The proportion of C. diff during the study period will be compared between arms.

Eligibility Criteria

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

Criteria

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 performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0 or 1 (>= 70% for Karnofsky/Lansky); use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age

• 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
    • 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) 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 infection
• Patient is allergic to the third or fourth generation celphalosporins, carbapenem, or aminoglycosides which are used to empirically treat LBP bacteremia

Contacts and Locations

  Show 37 Study Locations

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michael L Nieder; Children's Oncology Group

More Information

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT03057054 History of Changes
• Other Study ID Numbers: ACCL1633; NCI-2017-00208 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ACCL1633 ( Other Identifier: Childrens Oncology Group ); COG-ACCL1633 ( Other Identifier: DCP ); ACCL1633 ( Other Identifier: CTEP ); R01CA201788 ( U.S. NIH Grant/Contract ); UG1CA189955 ( U.S. NIH Grant/Contract )
• First Posted: February 17, 2017
• Last Update Posted: November 14, 2019
• Last Verified: November 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Graft vs Host Disease; Neoplasms; Immune System Diseases