TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801)
NCT ID: NCT03959241
Last Updated: 2024-04-04
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
431 participants
INTERVENTIONAL
2019-06-25
2022-09-19
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
NONE
Study Groups
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Tacrolimus/Methotrexate
Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
Tacrolimus
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.
Methotrexate
Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines.
Tacrolimus/MMF/PTCY
Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
Tacrolimus
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD
Mycophenolate Mofetil
MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present.
Cyclophosphamide
Cyclophosphamide \[50 mg/kg ideal body weight (IBW); if actual body weight (ABW) \< IBW, use ABW\] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day +4 post-transplant (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
Interventions
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Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate
Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
Tacrolimus
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD.
Methotrexate
Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines.
Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide
Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
Tacrolimus
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD
Mycophenolate Mofetil
MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present.
Cyclophosphamide
Cyclophosphamide \[50 mg/kg ideal body weight (IBW); if actual body weight (ABW) \< IBW, use ABW\] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day +4 post-transplant (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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/chronic myelomonocytic leukemia 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/small lymphocytic lymphoma with chemosensitive disease at time of transplantation
5. Patients with lymphoma \[follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma\] 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. Please note that THIS DOES NOT INCLUDE INVESTIGATIONAL AGENTS and maintenance therapy with investigational treatment requires approval by the study chairs.
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
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
18 Years
ALL
No
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Blood and Marrow Transplant Clinical Trials Network
NETWORK
National Cancer Institute (NCI)
NIH
National Marrow Donor Program
OTHER
Medical College of Wisconsin
OTHER
Responsible Party
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Principal Investigators
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Mary Horowitz, MD, MS
Role: STUDY_DIRECTOR
Center for International Blood and Marrow Transplant Research
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
City of Hope National Medical Center
Duarte, California, United States
University of California, San Francisco
San Francisco, California, United States
Stanford Hospital and Clinics
Stanford, California, United States
University of Florida College of Medicine (Shands)
Gainesville, Florida, United States
University of Miami
Miami, Florida, United States
H. Lee Moffitt Cancer Center
Tampa, Florida, United States
Emory University
Atlanta, Georgia, United States
Blood & Marrow Transplant Program at Northside Hospital
Atlanta, Georgia, United States
University of Chicago
Chicago, Illinois, United States
Loyola University
Maywood, Illinois, United States
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States
Indiana BMT - St. Francis Hospital
Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
University of Kansas Hospital
Kansas City, Kansas, United States
Johns Hopkins University
Baltimore, Maryland, United States
Dana Farber Cancer Institute/Brigham & Women's
Boston, Massachusetts, United States
Dana Farber Cancer Institute/Massachusetts General Hospital
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Karmanos Cancer Institute, Children's Hospital of Michigan
Detroit, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
Mayo Clinic - Rochester
Rochester, Minnesota, United States
Washington University/Barnes Jewish Hospital
St Louis, Missouri, United States
Mount Sinai Medical Center
New York, New York, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
University of North Carolina
Chapel Hill, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
University Hospitals of Cleveland/Case Western
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Ohio State/Arthur G. James Cancer Hospital
Columbus, Ohio, United States
Oregon Health & Science University
Portland, Oregon, United States
University of Pennsylvania Cancer Center
Philadelphia, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Baylor College of Medicine/The Methodist Hospital
Houston, Texas, United States
University of Texas, MD Anderson Cancer Research Center
Houston, Texas, United States
Virginia Commonwealth University, MCV Hospital
Richmond, Virginia, United States
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
University of Wisconsin Hospital & Clinics
Madison, Wisconsin, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Countries
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References
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Bolanos-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, Elmariah H, Rezvani AR, Gooptu M, Larkin KT, Shaffer BC, El Jurdi N, Loren AW, Solh M, Hall AC, Alousi AM, Jamy OH, Perales MA, Yao JM, Applegate K, Bhatt AS, Kean LS, Efebera YA, Reshef R, Clark W, DiFronzo NL, Leifer E, Horowitz MM, Jones RJ, Holtan SG; BMT CTN 1703 Investigators. Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis. N Engl J Med. 2023 Jun 22;388(25):2338-2348. doi: 10.1056/NEJMoa2215943.
Abedin S, Martens MJ, Bolanos-Meade J, Al Malki MM, Lian Q, Runaas L, Elmariah H, Gooptu M, Larkin KT, Shaffer BC, Loren AW, Solh M, Alousi AM, Jamy OH, Perales MA, Rezvani A, Bhatt A, El Jurdi N, Yao JM, Applegate K, Kean LS, Efebera YA, Reshef R, Clark W, Leifer E, Saber W, Horowitz MM, Jones RJ, Holtan SG, Hamadani M. Impact of posttransplant cyclophosphamide-based GVHD prophylaxis in patients 70 years and older: an update from BMT CTN 1703. Blood Adv. 2025 Jul 22;9(14):3495-3501. doi: 10.1182/bloodadvances.2025015964.
Holtan SG, Bolanos-Meade J, Al Malki MM, Wu J, Kitko CL, Reshef R, Rezvani AR, Shaffer BC, Solh MM, Yao JM, Runaas L, Elmariah H, Larkin KT, El Jurdi N, Gooptu M, Loren AW, Hall AC, Alousi AM, Jamy O, Clark W, Kean L, Bhatt AS, Perales MA, Applegate K, Efebera YA, Leifer E, Jones RJ, Horowitz MM, Mattila D, Saber W, Hamadani M, Martens MJ. Improved Patient-Reported Outcomes With Post-Transplant Cyclophosphamide: A Quality-of-Life Evaluation and 2-Year Outcomes of BMT CTN 1703. J Clin Oncol. 2025 Mar 10;43(8):912-918. doi: 10.1200/JCO.24.00921. Epub 2025 Jan 3.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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Blood and Marrow Transplant Clinical Trials Network Website
Other Identifiers
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BMT CTN 1703/1801
Identifier Type: -
Identifier Source: org_study_id
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