Clinical Trials /

TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)

NCT03959241

Description:

1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation. 1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Related Conditions:
  • Acute Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)
  • Official Title: A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate Versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation (BMT CTN #1703; Progress III); Companion Study: Microbiome and Immune Reconstitution in Cellular Therapies and Hematopoietic Stem Cell Transplantation (BMT CTN #1801; Mi-Immune)

Clinical Trial IDs

  • ORG STUDY ID: BMTCTN1703/1801
  • SECONDARY ID: 2U10HL069294-11
  • NCT ID: NCT03959241

Conditions

  • Acute Leukemia
  • Chronic Myelogenous Leukemia (CML)
  • Myelodysplasia
  • Lymphoma

Interventions

DrugSynonymsArms
TacrolimusPrograf®, FK506Tacrolimus/Methotrexate
MethotrexateMTXTacrolimus/Methotrexate
TacrolimusPrograf®, FK506Tacrolimus/MMF/PTCY
Mycophenolate MofetilCellCept®, MMFTacrolimus/MMF/PTCY
CyclophosphamideCytoxan®Tacrolimus/MMF/PTCY

Purpose

1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation. 1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Detailed Description

      1703: Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem
      cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the
      recipient's body. The current standard GVHD prophylaxis regimen for patients with hematologic
      malignancies undergoing HSCT involves a combination of immunosuppressive agents given for the
      first 6 months after transplant.

      The standard strategy of Tacrolimus/Methotrexate will be used as a control arm in comparison
      to one other treatment plan utilizing Tacrolimus/Mycophenolate Mofetil/Post-Transplant
      Cyclophosphamide. Study participants will receive an infusion of mobilized peripheral blood
      stem cell grafts on both arms. Study participants will be randomized to one of these two
      treatment arms.

      1801: A relationship between the intestinal microbiota and graft-versus-host disease (GVHD)
      has long been appreciated but is still not well understood. Mice transplanted in germ-free
      conditions or treated with gut-decontaminating antibiotics developed less severe GVHD.
      Clinical studies initially suggested a benefit from near-total bacterial decontamination, but
      later showed no clear benefit and this approach was discontinued in the early 1990s. Partial
      gut decontamination continues to be practiced at many centers. More recently, the advent of
      next-generation sequencing (NGS) has resulted in cheaper and easier characterization of
      complex microbial mixtures. This has led to a renewed interest in evaluating the relationship
      between the microbiota and human health and disease, including recipients of hematopoietic
      cell transplantation (HCT). Similarly, NGS has also contributed to significant advancements
      in the investigator's understanding of immune reconstitution in HCT patients and how this may
      impact clinica outcomes.

      The goal of this protocol is to test the primary hypothesis that the engraftment stool
      microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced
      intensity allogeneic HCT.
    

Trial Arms

NameTypeDescriptionInterventions
Tacrolimus/MethotrexateActive ComparatorMobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
  • Tacrolimus
  • Methotrexate
Tacrolimus/MMF/PTCYExperimentalMobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
  • Tacrolimus
  • Mycophenolate Mofetil
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          1. Age 18.0 years or older at the time of enrollment on Segment A

          2. Patients with acute leukemia or chronic myelogenous leukemia with no circulating
             blasts and with less than 5% blasts in the bone marrow

          3. Patients with myelodysplasia with no circulating blasts and with less than 10% blasts
             in the bone marrow (higher blast percentage allowed in MDS due to lack of differences
             in outcomes with <5% vs. 5-10% blasts in this disease)

          4. Patients with relapsed chronic lymphocytic leukemia with chemosensitive disease at
             time of transplantation

          5. Patients with lymphoma with chemosensitive disease at the time of transplantation

          6. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)

          7. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

               1. Sibling donor must be a 6/6 match for Human Leukocyte Antigen-A (HLA)-A and -B at
                  intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based
                  typing, and must be willing to donate peripheral blood stem cells and meet
                  institutional criteria for donation.

               2. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and -DRB1 at high
                  resolution using DNA-based typing. Unrelated donor must be willing to donate
                  peripheral blood stem cells and meet National Marrow Donor Program (NMDP)
                  criteria for donation.

          8. Cardiac function: Left ventricular ejection fraction at least 45%

          9. Estimated creatinine clearance acceptable per institutional guidelines

         10. Pulmonary function: Diffusing capacity of lung for carbon monoxide (DLCO) corrected
             for hemoglobin at least 40% and forced expiratory volume at one second (FEV1)
             predicted at least 50%

         11. Liver function acceptable per institutional guidelines

         12. Karnofsky Performance Score at least 60%

         13. Female patients (unless postmenopausal for at least 1 year before the screening visit,
             or surgically sterilized), agree to practice two (2) effective methods of
             contraception at the same time, or agree to completely abstain from heterosexual
             intercourse, from the time of signing the informed consent through 12 months
             post-transplant (see Section 2.6.4 for definition of postmenopausal)

         14. Male patients (even if surgically sterilized), of partners of women of childbearing
             potential must agree to one of the following: practice effective barrier contraception
             (see Section 2.6.4 for list of barrier methods), or abstain from heterosexual
             intercourse from the time of signing the informed consent through 12 months
             post-transplant

         15. Plans for the use of post-transplant maintenance therapy must be disclosed upon
             enrollment and must be used irrespective of the outcome of the randomization

         16. Voluntary written consent obtained prior to the performance of any study-related
             procedure that is not a part of standard medical care, with the understanding that
             consent may be withdrawn by the patient at any time without prejudice to future
             medical care.

        Exclusion Criteria:

          1. Prior allogeneic transplant

          2. Active central nervous system (CNS) involvement by malignant cells

          3. Patients with secondary acute myeloid leukemia arising from myeloproliferative
             disease, including chronic myelomonocytic leukemia (CMML)

          4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking
             medication and with progression or no clinical improvement) at time of enrollment.

          5. Presence of clinically significant fluid collection (ascites, pleural or pericardial
             effusion) that interferes with methotrexate clearance or makes methotrexate use
             contraindicated

          6. Patients seropositive for human immunodeficiency virus (HIV) with detectable viral
             load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.

          7. Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
             ischemia.

          8. Female patients who are pregnant (as per institutional practice) or lactating

          9. Patients with a serious medical or psychiatric illness likely to interfere with
             participation in this clinical study

         10. Patients with prior malignancies except resected non-melanoma skin cancer or treated
             cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously
             will be allowed. Cancer treated with curative intent < 5 years previously must be
             reviewed and approved by the Protocol Officer or Chairs.

         11. Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:GVHD-free, Relapse-free survival (GRFS) probability
Time Frame:1 year
Safety Issue:
Description:The primary endpoint is GRFS as a time to event endpoint from the time of randomization. All transplanted patients will be followed for the primary endpoint for one year; however the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the intent-to-treat principle.

Secondary Outcome Measures

Measure:Acute GVHD
Time Frame:Days 100, 180, and 1 year
Safety Issue:
Description:Incidence of acute GVHD grade II-IV and grade III-IV at Days 100, 180 and 1 year will be estimated with 95% confidence intervals for each treatment group - using the cumulative incidence estimate, treating death prior to aGVHD as a competing event.
Measure:Chronic GVHD
Time Frame:1 year
Safety Issue:
Description:Incidence of chronic GVHD at 1 year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death prior to chronic GVHD as a competing event.
Measure:Immunosuppression-free Survival
Time Frame:1 year
Safety Issue:
Description:Proportions of patients alive, relapse free, and off immune suppression at 1 year will be described for each treatment group, along with 95% confidence intervals.
Measure:Hematologic Recovery
Time Frame:Days 28 and 100
Safety Issue:
Description:Probabilities of neutrophil recovery by Day 28 and Day 100 will be described with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death as a competing event.
Measure:Donor Cell Engraftment
Time Frame:Days 28 and 100
Safety Issue:
Description:Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized treatment arms will be described numerically as median and range for those evaluable as well as according to proportions with full (>95% donor cell), mixed (5.0-94.9% donor cells), graft rejection (<5%), or death prior to assessment of donor chimerism.
Measure:Disease Relapse or Progression
Time Frame:1 year
Safety Issue:
Description:Incidence of disease relapse or progression at 1 year will be estimated with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death prior to disease relapse as a competing event.
Measure:Transplant-related Mortality
Time Frame:Days 100, 180 and 1 year
Safety Issue:
Description:Incidence of transplant-related mortality (TRM) at Days 100, 180 and 1 year will be estimated for each treatment group using the cumulative incidence estimate, treating disease relapse or progression as a competing event.
Measure:Toxicity grade over time
Time Frame:1 year
Safety Issue:
Description:All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of toxicity as well as the peak grade overall. Toxicity frequencies up to 1 year will be described for each time interval as well as cumulative over time.
Measure:Infections
Time Frame:1 year
Safety Issue:
Description:The number of infections and the number of patients experiencing infections will be tabulated for each randomized treatment arm by type of infection, severity, and time period after transplant.
Measure:Disease-free Survival
Time Frame:1 year
Safety Issue:
Description:Kaplan-Meier curves will be constructed to estimate 1 year disease free survival probabilities for each treatment group.
Measure:Overall Survival
Time Frame:1 year
Safety Issue:
Description:Kaplan-Meier curves will be constructed to estimate 1 year overall survival probabilities for each treatment group.
Measure:Post-Transplant Lymphoproliferative Disease (PTLD)
Time Frame:1 year
Safety Issue:
Description:Probabilities of PTLD at 1-year post transplant will be described with 95% confidence intervals for each treatment group using the cumulative incidence estimate, treating death as a competing event.
Measure:Patient-Reported Outcomes (PRO)
Time Frame:Days 100, 180 and 1 year
Safety Issue:
Description:Patient-Reported Outcomes will be measured at baseline then at Days 100, 180 and one year post HCT. Using a repeated measures model, we will compute PRO composite scores and compare treatments after adjustment for baseline characteristics as described for the primary endpoint.
Measure:Diversity of Immune Repertoire
Time Frame:3, 6, 12, and 24 Months
Safety Issue:
Description:To study the diversity of the immune repertoire post-transplant and correlate with clinical outcomes, as well as study the impact on immune recovery of the method of GVHD prophylaxis and other patient and transplant factors.
Measure:Diversity and Composition of the Gut Microbiome
Time Frame:3, 6, 12, and 24 Months
Safety Issue:
Description:To study the diversity and composition of the gut microbiome post-transplant and correlate with clinical outcomes, as well as study the impact on the microbiome of the method of GVHD prophylaxis and other patient and transplant factors.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medical College of Wisconsin

Trial Keywords

  • Acute Leukemia
  • Chronic Myelogenous Leukemia (CML)
  • Myelodysplasia (MDS)
  • Lymphoma
  • GVHD prophylaxis
  • Acute GVHD

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