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

NCT03959241 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: BMT CTN 1703/18012U10HL069294-11
• Study Type: interventional
• Target: 431
• Locations: 1 country
• Sites: 39

Brief Summary

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS) at One Year

  The primary endpoint is GRFS as a time to event endpoint from randomization. All randomized patients will be followed for one year; however, the primary endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the randomized population. An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause, whichever comes first. Time to event analyses were conducted. An unadjusted Kaplan-Meier analysis was done. Additionally, a multivariate Cox regression model adjusting for the following pre-specified covariates: age group (\< 65 vs. 65+), disease risk index (low, intermediate, high/very high), planned RIC conditioning regimen (Fludarabine/Busulfan, Fludarabine/Melphalan, Other), donor type/HLA matching score (related 6/6, unrelated 7/8, unrelated 8/8), and planned use of post-transplant maintenance therapy (Yes vs. no).

  1 year post randomization

Secondary Outcomes (23)

• Percentage of Participants With Grades II-IV and III-IV Acute GVHD at Day 100 Post-transplant

  Days 100 post-transplant

• Participants With Maximum Acute GVHD at One Year Post-transplant

  One year post-transplant

• Participants With Maximum Stage of Skin, Lower GI, and Liver at Day 100 Post-transplant

  Day 100 post-transplant

• Participants With Maximum Stage of Upper GI at Day 100 Post-transplant

  Day 100 post-transplant

• Percentage of Participants With Chronic GVHD Post-transplant

  6, 12 months post-transplant

Study Arms (2)

Tacrolimus/Methotrexate

ACTIVE COMPARATOR

Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate

Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate; Drug: Tacrolimus; Drug: Methotrexate

Tacrolimus/MMF/PTCY

EXPERIMENTAL

Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide

Procedure: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Drug: Cyclophosphamide

Interventions

Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate PROCEDURE

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.

Also known as: HSCT

Tacrolimus/Methotrexate

Tacrolimus DRUG

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.

Also known as: Prograf®, FK506

Tacrolimus/Methotrexate

Methotrexate DRUG

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.

Also known as: MTX

Tacrolimus/Methotrexate

Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide PROCEDURE

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.

Also known as: HSCT

Tacrolimus/MMF/PTCY

Mycophenolate Mofetil DRUG

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.

Also known as: CellCept®, MMF

Tacrolimus/MMF/PTCY

Cyclophosphamide DRUG

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).

Also known as: Cytoxan®

Tacrolimus/MMF/PTCY

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18.0 years or older at the time of enrollment on Segment A
• Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts and with less than 5% blasts in the bone marrow
• 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)
• Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with chemosensitive disease at time of transplantation
• 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
• Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)
• Patients must have a related or unrelated peripheral blood stem cell donor as follows:
• 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.
• 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.
• Cardiac function: Left ventricular ejection fraction at least 45%
• Estimated creatinine clearance acceptable per institutional guidelines
• 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%
• Liver function acceptable per institutional guidelines
• Karnofsky Performance Score at least 60%
• 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)

You may not qualify if:

• Prior allogeneic transplant
• Active central nervous system (CNS) involvement by malignant cells
• Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including chronic myelomonocytic leukemia (CMML)
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
• Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
• Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. HIV+ patients with an undetectable viral load on antiviral therapy are eligible.
• 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.
• Female patients who are pregnant (as per institutional practice) or lactating
• Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
• 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.
• Planned use of antithymocyte globulin (ATG) or alemtuzumab in conditioning regimen

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• National Cancer Institute (NCI): collaborator
• National Marrow Donor Program: collaborator

Study Sites (39)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Stanford Hospital and Clinics

Stanford, California, 94305, United States

Location

University of Florida College of Medicine (Shands)

Gainesville, Florida, 32610, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

H. Lee Moffitt Cancer Center

Tampa, Florida, 33624, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Blood & Marrow Transplant Program at Northside Hospital

Atlanta, Georgia, 30342, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Loyola University

Maywood, Illinois, 60153, United States

Location

Indiana University Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Indiana BMT - St. Francis Hospital

Indianapolis, Indiana, 46327, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242-1009, United States

Location

University of Kansas Hospital

Kansas City, Kansas, 66160, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute/Brigham & Women's

Boston, Massachusetts, 02115, United States

Location

Dana Farber Cancer Institute/Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Karmanos Cancer Institute, Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University/Barnes Jewish Hospital

St Louis, Missouri, 63110, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10174, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

University Hospitals of Cleveland/Case Western

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State/Arthur G. James Cancer Hospital

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239-3098, United States

Location

University of Pennsylvania Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Baylor College of Medicine/The Methodist Hospital

Houston, Texas, 77030, United States

Location

University of Texas, MD Anderson Cancer Research Center

Houston, Texas, 77030, United States

Location

Virginia Commonwealth University, MCV Hospital

Richmond, Virginia, 23298, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109-1024, United States

Location

University of Wisconsin Hospital & Clinics

Madison, Wisconsin, 53792-5156, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53211, United States

Location

Related Publications (3)

• 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.

  PMID: 37342922 BACKGROUND

• 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.

  PMID: 40305657 DERIVED

• 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.

  PMID: 39752608 DERIVED

Related Links

• Blood and Marrow Transplant Clinical Trials Network Website

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Anemia, Refractory, with Excess of Blasts; Lymphoma

Interventions

Tacrolimus; Methotrexate; Mycophenolic Acid; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Adam Mendizabal, PhD
• Organization: The Emmes Company, LLC

amendizabal@emmes.com

(301) 251-1161

Study Officials

• Mary Horowitz, MD, MS

  Center for International Blood and Marrow Transplant Research

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks of random sizes.

Study Record Dates

• First Submitted: May 20, 2019
• First Posted: May 22, 2019
• Study Start: June 25, 2019
• Primary Completion: September 19, 2022
• Study Completion: September 19, 2022
• Last Updated: April 4, 2024
• Results First Posted: January 12, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public

Locations

US (39)