Acute Leukemia of Ambiguous Lineage, Acute Lymphoblastic Leukaemia, Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
MAST
Brief summary
The goal of this clinical trial is to test the ability to restore gut microbiota to healthier levels in patients with blood cancers scheduled to have stem cell transplant. The main questions it aims to answer are: * Tolerability and acceptability of intestinal microbiota transplantation (IMT) versus placebo (as assessed via patient perspective questionnaires * Changes in gut microbiome diversity across all timepoints * Markers of general health, infective/microbiological and haematological outcomes including, days of fever, admission to intensive care unit, survival, non-relapsed mortality, and incidence of graft-versus-host disease across all time points measured. Participants will be asked at their routine follow up visits to, * Provide stool, urine and blood samples at the scheduled study visits * Complete questionnaires at selected visits * Swallow either Placebo or IMT capsules once at the second study visit which will occur 2 weeks prior to the stem cell transplant (+/-3 days) Researchers will compare IMT capsules and Placebo to investigate the change in gut microbiota diversity.
Interventions
DRUGEBX-102
EBX-102 is a white size 0 gastro-resistant hydroxypropyl methylcellulose (HPMC) capsule containing communities of dried, intestinal microorganisms extracted from rigorously screened pooled human stool samples obtained from volunteer accredited donors.
DRUGPlacebo
The capsules contain inactive ingredients microcrystalline cellulose and magnesium stearate.
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. \- Patients aged 18 years and over with a morphological documented diagnosis of ALL, acute myeloid leukemia (AML), AL of ambiguous lineage, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and CML in blast phase (Appendix 2) who are deemed fit for allogenic HCT with one of the following disease characteristics: ALL, AML, AL of ambiguous lineage * Patients in first complete remission (CR1) or second complete remission (CR2) including complete remission with incomplete blood count recovery with \< 5% blasts (Appendix 2) * Secondary leukaemia (defined as previous history of MDS, antecedent haematological disease or chemotherapy exposure) in CR1 or CR2 defined as \< 5% blasts (Appendix 2) MDS and CMML * Patients with advanced or high risk MDS with an International Prognostic Scoring System (IPSS-M) moderate high or higher including intermediate or high risk CMML who have \< 5% blasts at the time of randomisation (Appendix 2) CML in blast phase * Patients with Philadelphia or BCR:ABL1 positive chronic myeloid leukaemia (CML) in blast phase defined by the presence of ≥ 20% blasts in blood or bone marrow who have achieved second chronic phase with \< 5% blasts (Appendix 2). 2. Patients must have completed minimum of two cycles of intensive chemotherapy prior to trial enrolment (Appendix 1) 3. Patients must have received broad-spectrum antibiotics within 3 months prior to trial enrolment 4. Patients must be considered suitable/fit to undergo allogeneic hematopoietic cell transplantation (HCT) as clinically judged by the Local investigator 5. Patients with an Karnofsky performance status score 60 or above (Appendix 3) 6. Females of and male patients of reproductive potential (i.e., not post-menopausal or surgically sterilised) must use appropriate, highly effective, contraception from the point of commencing therapy until 6 months after treatment 7. Patients have given written informed consent 8. Patients willing and able to comply with scheduled study visits and laboratory tests
Exclusion criteria
1. Patients with contraindications to receiving allogeneic HCT. 2. Female patients who are pregnant or breastfeeding. All women of childbearing potential must have a negative pregnancy test before commencing treatment. 3. Adults of reproductive potential not willing to use appropriate, highly effective, contraception during the specified period. 4. Patients with renal or hepatic impairment as clinically judged by the Local Investigator. 5. Patients with active infection, HIV-positive or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV). 6. Patients with a concurrent active malignancy or a prior malignancy, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ, incidental histologic finding of prostate cancer (T1a or T1b using the tumour, node, metastasis (TNM) clinical staging system), previous MDS, CMML, Myeloproliferative neoplasms (MPN) resulting in secondary AML. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent \< 5 years previously will not be allowed. 7. Swallowing difficulties that may preclude safe use of IMT capsules. 8. Administration of IMT within 3 months prior to enrolment (probiotic administration prior to enrolment is allowed but should be recorded at screening). 9. Patients taking probiotics after enrolment to the trial. 10. Gastrointestinal disorders and diseases, including delayed gastric emptying, coeliac disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, chronic diarrhoea, and colonic perforation or fistula. 11. Any autoimmune disease requiring, or that may require, systemic treatment with steroids and/or other immunosuppressants/immunomodulators. 12. Significant bleeding disorder (ALL, AML, AL of ambiguous lineage, MDS, CMML, and CML satisfying inclusion criteria are not excluded). 13. Anaphylactic food allergy. 14. Requirement for vasopressors. 15. Valvular heart disease or known structural defects of the heart. 16. Known severe allergy to capsule components.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in gut microbiota diversity using Inverse Simpsons Index | Screening - up to 42 before stem cell transplantation (HCT) and Assessment 5 - Day 28(+/-3) post stem cell transplantation (HCT) | Ecological metric to measure diversity in the gut microbiome in samples collected at two time points. It considers both the number of species present (richness) and their relative abundance (evenness). The Inverse index scale ranges from 0-1 with higher ranges indicating higher diversity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gut Microbiome Diversity - Alpha diversity | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured via changes in Chao-1 , Shannon index and Faith's PD to estimate the richness and functional composition across all timepoints |
| Alpha Diversity - Chao1 Index | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | A non-parametric method for estimating Species Richness: referring to the total number of different species present in the gut microbiome, particularly useful for accounting for undetected species.points |
| Alpha Diversity - Shannon Index | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | An ecological metric used to measure which combines both, Species Richness: referring to the total number of different species present in the gut microbiome. Species Evenness: this indicates how evenly the species are distributed. A higher index value implies higher evenness and richness. |
| Alpha Diversity - Faiths Phylogenetic Diversity (Faiths PD) | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | An ecological metric used to measure, Species Richness: referring to the total number of different species present in the gut microbiome. Faiths PD also uses the phylogenetic tree of the identified species to measure the total evolutionary distance. A higher Faith's PD value indicates a wider range of evolutionary diversity |
| Beta Diversity - Aitchison Distance | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Ecological metric used to compare the distance in compositions in stool samples collected at different time points will with the baseline stool sample. Larger distances might indicate differences in bacterial communities present in the gut microbiome |
| Gut Microbiome Taxonomic Composition | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured using shallow shotgun sequencing which indicates the specific bacterial types and relative abundancies. stool samples collected at different time points will be compared with the baseline stool sample. |
| Quality of life EQ-5D-5L | Screening up to Day-42, Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Quality of live measured by standardised EQ-5D-5L questionnaire which assesses five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression on a scale from 0 (worst health imaginable) to 100 (best health imaginable |
| Quality of Life EORTC-QLQ-C30 | Screening up to Day-42, Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Quality of life measured by standardised EORTC-QLQ-C3O Questionnaire Contains 30 questions grouped into 15 functional scales. Each scale is scored individually based on the answers, resulting in a score between 0 and 100. A higher score indicates better quality of life in that specific m |
| Infective Haematological Outcomes - Fever Occurrence | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Fever: Rise in body temperature above the normal range 38°C (100.4°F) or higher reported across all study time points post screening. |
| Infective Haematological Outcomes - Fever CTCAE Grade | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured by the number of reported occurrences of grade I - IV following the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading system |
| Infective Haematological Outcomes - Infection | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured by reported occurrences of bloodstream infections and urinary tract infections across all time points. |
| Infective Haematological Outcomes - Multi drug Resistant Bacterial Colonisation (MDROs) | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the number of reported deaths not caused by relapse or progression |
| Markers of general health - ITU Admission | Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the total number days spent in an intensive care unit (ITU) from treatment to end of study |
| Markers of General Health - Severity of Mucositis | The outcome will be assessed at Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the number of reported occurrences of mucositis grade III and above following the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading system post stem cell transplantation. |
| Markers of General Health -Occurrence of Severe Acute Kidney Injury (AKI) | The outcome will be assessed at Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the reported incidence of severe acute kidney post stem cell transplantation. |
| Markers of General Health - Occurrence of Severe liver dysfunction | The outcome will be assessed at Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the reported incidence of severe liver dysfunction post stem cell transplantation. |
| Markers of general health - Use of Parenteral Nutrition | The outcome will be assessed at Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured by the reported use of parenteral nutrition treatment post stem cell transplantation |
| Neutrophil and platelet engraftment data | Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Neutrophil and platelet engraftment data as defined by European Group for Blood and Marrow Transplantation (EBMT) will be routinely collected |
| Recovery of T-cell Chimaerisms, | Follow up Assessments: Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | T-cell count assessed by the lymphocyte subset analysis and immunoglobulin levels will be recorded at follow-up assessments. |
| Haematological Outcomes - Non-relapsed mortality | Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Assessed by the number of reported deaths not caused by relapse or progression post stem cell transplantation |
| Haematological Outcomes - Occurrence Graft vs Host Disease | Follow up Assessments: Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured by the reported occurrence of Graft vs Host Disease at all follow up assessments. |
| Haematological Outcomes - Severity of graft vs Host Disease | Follow up Assessments: Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured using the National Institutes of Health (NIH) Chronic/Acute GvHD Global Severity classification at all follow up assessments. |
| Overall Survival | Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Overall Survival (OS) - Measured from the time of the stem cell transplant date to the reporting of death from any cause up to 1 year post stem cell |
| Graft-versus disease-free relapse-free survival | Days Post HCT: Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Graft-versus disease-free relapse-free survival (GFRS) - Measured from the time of the stem cell transplant date to the reporting of the first occurrence of either relapse or any grade of graft vs host disease (GVHD) |
| Infective Haematological Outcomes - Antibiotic Use | All timepoints, Screening up to Day-42, Day -7(+/-2), Day 0(+/-1), Day 7(+/-3), Day 14(+/-3), Day 28(+/-3), Day 100(+/-7), Day 200(+/-7) & Day 365(+/-14) | Measured by reported use of antibiotics to treat an infection diagnosis at all study timepoints. |
Countries
United Kingdom
Contacts
Primary ContactClinical Trials Coordinator
Backup ContactJulian Marchesi
Outcome results
None listed