Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)
A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN #1203; Progress I)
2 other identifiers
interventional
279
1 country
30
Brief Summary
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Aug 2014
Typical duration for phase_2
30 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 1, 2014
CompletedStudy Start
First participant enrolled
August 1, 2014
CompletedFirst Posted
Study publicly available on registry
August 4, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 1, 2017
CompletedStudy Completion
Last participant's last visit for all outcomes
October 1, 2017
CompletedResults Posted
Study results publicly available
January 23, 2019
CompletedJanuary 23, 2019
December 1, 2017
3.2 years
August 1, 2014
December 4, 2018
January 2, 2019
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Percentage of Participants With GVHD/Relapse or Progression-free Survival (GRFS)
GRFS is defined as being free of grade III-IV acute GVHD onset, chronic GVHD onset requiring systemic immunosuppressive therapy, disease relapse or progression, and death from any cause.
1 Year Post-transplant
Secondary Outcomes (13)
Percentage of Participants With Grade II-IV Acute GVHD
Day 180 Post-transplant
Percentage of Participants With Grade III-IV Acute GVHD
Day 180 Post-transplant
Percentage of Participants With Chronic GVHD
1 Year Post-transplant
Percentage of Participants With Chronic GVHD Requiring Immunosupressive Therapy
1 Year Post-transplant
Percentage of Participants With Disease Relapse or Progression
1 Year Post-transplant
- +8 more secondary outcomes
Study Arms (3)
Tacrolimus/Methotrexate/Bortezomib
EXPERIMENTALParticipants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Tacrolimus/Methotrexate/Maraviroc
EXPERIMENTALParticipants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Tacrolimus/MMF/Cyclophosphamide
EXPERIMENTALParticipants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Interventions
Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting 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. The dose should be adjusted accordingly to maintain a suggested level of 5-15 ng/mL. If patients are on medications which alter the metabolism of tacrolimus (e.g. azoles), 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 HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus by Day 180 post HSCT if there is no evidence of active GVHD.
Tacrolimus will be given orally at a dose of 0.05 mg/kg or intravenously at a dose of 0.03 mg/kg starting Day +5. 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 HSCT 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 HSCT if there is no evidence of active GVHD.
Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of maraviroc. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
Methotrexate will be administered, per institutional practices, 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. The Day +1 dose of methotrexate will be given at least 24 hours after the hematopoietic stem cell infusion and at least 30 minutes after the first dose of bortezomib. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices.
Maraviroc will be dosed at 300 mg orally twice a day and will start on Day -3 prior to hematopoietic stem cell infusion, and continue until Day 30 post HSCT. If the patient requires a two-day stem cell infusion, maraviroc treatment will end 30 days after the first infusion day.
Bortezomib will be administered at the dose of 1.3 mg/m2 based upon actual body weight (ABW) as an approximately 3-5 second IV push on Days +1, +4, and +7 after hematopoietic stem cell infusion. There must be at least 72 hours between each dose of bortezomib. Subcutaneous administration of bortezomib is not allowed on this protocol.
MMF will be given at a dose of 15 mg/kg three times a day (TID) based upon ABW 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.
Hydration prior to cyclophosphamide may be given according to institutional standards. Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide \[50 mg/kg ideal body weight (IBW); if ABW \< IBW, use ABW\] will be given on Day 3 post-transplant (between 60 and 72 hours after the start of the HSCT) 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).
Eligibility Criteria
You may qualify if:
- Age 18-75 years (patient is older than 18.0 and less than 76.0 years old)
- Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow.
- Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin's Lymphoma,or mantle cell lymphoma with chemosensitive disease at 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 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 be medically cleared to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
- Cardiac function: Ejection fraction at rest ≥ 45%
- Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
- Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
- Liver function: total bilirubin \< 1.5 x the upper limit of normal and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 1.5x the upper limit of normal.
- Female subjects (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).
- Male subjects (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.
- Signed informed consent
You may not qualify if:
- Prior allogeneic transplant
- Karnofsky Performance Score \< 70%
- Active central nervous system (CNS) involvement by malignant cells
- Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
- Presence of fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
- Patients with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia)
- Patients seropositive for the human immunodeficiency virus (HIV)
- Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification tests (NAAT)
- Patients with hypersensitivity to bortezomib, boron or mannitol
- Patients with ≥ grade 2 sensory peripheral neuropathy
- Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
- Female patients who are lactating or pregnant
- Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
- Patients with prior malignancies except resected basal cell carcinoma 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 will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
- Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen.
- +3 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (30)
City of Hope National Medical Center
Duarte, California, 91010, United States
Stanford Hospital and Clinics
Stanford, California, 94305, United States
University of Florida College of Medicine (Shands)
Gainesville, Florida, 32611, United States
H. Lee Moffitt Cancer Center
Tampa, Florida, 33624, United States
Emory University
Atlanta, Georgia, 30322, United States
BMT Program at Northside Hospital
Atlanta, Georgia, 30342, United States
Loyola University Medical Center
Maywood, Illinois, 60153, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242, United States
University of Kansas Hospital
Westwood, Kansas, 66205, United States
Johns Hopkins University
Baltimore, Maryland, 22218, United States
Dana Farber Cancer Institute/Massachusetts General Hospital
Boston, Massachusetts, 02114, United States
Dana Farber Cancer Institute/Brigham & Women's
Boston, Massachusetts, 02215, United States
Karmanos Cancer Institute/BMT
Detroit, Michigan, 48201, United States
University of Minnesota
Minneapolis, Minnesota, 55455, United States
Mayo Clinic - Rochester
Rochester, Minnesota, 55905, United States
Washington University/Barnes Jewish Hospital
St Louis, Missouri, 63130, United States
University of Nebraska Medical Center
Omaha, Nebraska, 68198, United States
Roswell Park Cancer Institute
Buffalo, New York, 14263, United States
Memorial Sloan-Kettering Cancer Center
Manhattan, New York, 10065, United States
University of North Carolina Hospital at Chapel Hill
Chapel Hill, North Carolina, 27514, United States
Cleveland Clinic Foundation
Cleveland, Ohio, 44106, United States
University Hospitals of Cleveland/Case Western
Cleveland, Ohio, 44106, United States
Ohio State/Arthur G. James Cancer Hospital
Columbus, Ohio, 43210, United States
Oregon Health & Science University
Portland, Oregon, 97239, United States
University of Pennsylvania Cancer Center
Philadelphia, Pennsylvania, 19104, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
University of Texas/MD Anderson Cancer Center
Houston, Texas, 77030, United States
Texas Transplant Institute
San Antonio, Texas, 78229, United States
University of Utah Med School
Salt Lake City, Utah, 84112, United States
Virginia Commonwealth University MCV Hospitals
Richmond, Virginia, 23284, United States
Related Publications (3)
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.
PMID: 7581076BACKGROUNDFilipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
PMID: 16338616BACKGROUNDBolanos-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, Alousi AM, Antin JH, Arai S, Bickett K, Chen YB, Damon LE, Efebera YA, Geller NL, Giralt SA, Hari P, Holtan SG, Horowitz MM, Jacobsohn DA, Jones RJ, Liesveld JL, Logan BR, MacMillan ML, Mielcarek M, Noel P, Pidala J, Porter DL, Pusic I, Sobecks R, Solomon SR, Weisdorf DJ, Wu J, Pasquini MC, Koreth J. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019 Mar;6(3):e132-e143. doi: 10.1016/S2352-3026(18)30221-7.
PMID: 30824040DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Adam Mendizabal, PhD
- Organization
- The Emmes Corporation
Study Officials
- STUDY DIRECTOR
Mary Horowitz, MD
Center for International Blood and Marrow Transplant Research
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- PREVENTION
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 1, 2014
First Posted
August 4, 2014
Study Start
August 1, 2014
Primary Completion
October 1, 2017
Study Completion
October 1, 2017
Last Updated
January 23, 2019
Results First Posted
January 23, 2019
Record last verified: 2017-12
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL
- Time Frame
- Within 6 months of official study closure at participating sites.
- Access Criteria
- Available to the public
Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc where indicated).