Acute Graft Versus Host Disease, Hematopoietic and Lymphatic System Neoplasm, Leukemia, Lymphoma
Conditions
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.
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.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo alloHCT
BIOLOGICALLactobacillus plantarum strain 299
Given PO or via NJ, NG or G tube
BIOLOGICALLactobacillus plantarum strain 299v
Given PO or via NJ, NG or G tube
OTHERPlacebo Administration
Given PO or via NJ, NG or G tube
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Stage 1-4 Gastrointestinal (GI) Acute Graft Versus Host Disease (aGVHD) | Up to 120 days post stem cell infusion | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Blood Stream Infection | Up to 120 days post stem cell infusion | The risk of mucosal barrier blood stream infections will be compared between two groups. |
| Incidence of Clostridium Difficile (C. Diff)-Associated Diarrhea | Up to 120 days post stem cell infusion | Proportion of C. diff-associated diarrhea during the study period will be compared between arms. |
| Serum Levels of Citrulline | Up to 120 days post stem cell infusion | 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. |
| Bacterial Genes and Pathways, and Bacterial Metabolites (Blood/Stool Measures of Intestinal Flora - Function and Phylogenetic Composition) | Up to 120 days post stem cell infusion | 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. |
| Incidence of Grade II-IV Overall Graft Versus Host Disease | Up to 120 days post stem cell infusion | 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. |
| Levels of Pro-inflammatory Cytokines | 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 by comparing levels across arms. |
| Hospital Days | 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. |
| Incidence of Lactobacillus Plantarum Bacteremia | 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 patients experiencing lactobacillus plantarum bacteremia during the study period will be compared between arms. |
| Blood/Stool Measures of Intestinal Flora Assessed Using Sequencing | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Enrollment through day 120 post-stem cell infusion
Participants by arm
| Arm | Count |
|---|---|
| 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. | 85 |
| 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. | 88 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 4 |
| Overall Study | Ineligible | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Arm I (Lactobacillus Plantarum, alloHCT) | Arm II (Placebo, alloHCT) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 74 Participants | 76 Participants | 150 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 23 Participants |
| Age, Continuous | 10.7 years STANDARD_DEVIATION 6 | 12.1 years STANDARD_DEVIATION 5.6 | 11.4 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 21 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 61 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 13 Participants | 27 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 11 Participants | 26 Participants |
| Race (NIH/OMB) White | 49 Participants | 60 Participants | 109 Participants |
| Region of Enrollment Canada | 7 participants | 5 participants | 12 participants |
| Region of Enrollment United States | 78 participants | 83 participants | 161 participants |
| Sex: Female, Male Female | 29 Participants | 35 Participants | 64 Participants |
| Sex: Female, Male Male | 56 Participants | 53 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 85 | 4 / 88 |
| other Total, other adverse events | 9 / 84 | 9 / 87 |
| serious Total, serious adverse events | 5 / 84 | 8 / 87 |
Outcome results
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.
Time frame: Up to 120 days post stem cell infusion
Population: 2 patients were excluded because they were not eligible (1 patient from Group 1 and 1 patient from Group 2). 2 patients were excluded because they did not initiate treatment (1 patient from Group 1 and 1 patient from Group 2). 10 patients were excluded because they never received a stem cell infusion within 6 months of enrollment (5 patients from Group 1 and 5 patients from Group 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Lactobacillus Plantarum, alloHCT) | Proportion of Participants With Stage 1-4 Gastrointestinal (GI) Acute Graft Versus Host Disease (aGVHD) | 0.15 Proportion of patients |
| Arm II (Placebo, alloHCT) | Proportion of Participants With Stage 1-4 Gastrointestinal (GI) Acute Graft Versus Host Disease (aGVHD) | 0.15 Proportion of patients |
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
Incidence of Blood Stream Infection
The risk of mucosal barrier blood stream infections will be compared between two groups.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
Incidence of Clostridium Difficile (C. Diff)-Associated Diarrhea
Proportion of C. diff-associated diarrhea during the study period will be compared between arms.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion
Other Pre-specified
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.
Time frame: Up to 120 days post stem cell infusion