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Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)

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ClinicalTrials.gov Identifier: NCT02208037
Recruitment Status : Completed
First Posted : August 4, 2014
Last Update Posted : April 6, 2018
Sponsor:
Collaborators:
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)

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.

Condition or disease Intervention/treatment Phase
Acute Leukemia Chronic Myelogenous Leukemia Myelodysplasia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Lymphoma, B-Cell Lymphoma, Follicular Lymphoma, Large B-Cell, Diffuse Hodgkin's Lymphoma Drug: Tacrolimus (ARM with Methotrexate) Drug: Tacrolimus (ARM with MMF and Cyclophosphamide) Drug: Methotrexate (ARM with Maraviroc) Drug: Methotrexate (ARM with Bortezomib) Drug: Maraviroc Drug: Bortezomib Drug: Mycophenolate mofetil Drug: Cyclophosphamide Phase 2

Detailed Description:

GVHD is a complication that can occur after a bone marrow or stem cell transplant. The transplant recipient's body is attacked by the newly introduced cells. Only about 40% of patients with acute GVHD have durable responses when treated with corticosteroid therapy. A strategy that helps fewer people suffer from GVHD, without other adverse effects, would be an effective approach to improve survival after allogeneic transplantation.

GVHD incidence can be decreased with various treatment plans. Early transplants were done using post-transplant methotrexate to prevent GVHD. Another drug, cyclosporine, was later shown to work better than methotrexate. Then doctors discovered that the combined use of cyclosporine and methotrexate worked even better than either agent alone. More recently, other calcineurin-inhibitors, such as tacrolimus have been developed as GVHD prophylactic agents due to favorable toxicity profiles in comparison with cyclosporine. Studies have been conducted to compare available treatment combinations for related and unrelated donors. The combination of tacrolimus/methotrexate remains a standard for GVHD prophylaxis.

However, improved GVHD prophylaxis remains a significant clinical need in HSCT. The current clinical trial will test three novel GVHD prophylaxis approaches: tacrolimus/methotrexate and bortezomib (Tac/MTX/Bort), tacrolimus/methotrexate and maraviroc (Tac/MTX/MVC) and tacrolimus/mycophenolate mofetil and cyclophosphamide (Tac/MMF/Cy). This randomized Phase II clinical trial will compare each intervention arm with a Tac/MTX control.

This study will enroll people who have a cancer of the blood or lymph glands and a stem cell transplant is a treatment option. The study will take at least two years and will include 270 participants - 90 participants in each of three treatment groups. The purpose of this study is to compare three combinations of medications to see whether one or more of them are better than the current standard of care (Tacrolimus/Methotrexate) to prevent GVHD.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 279 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Multi-center Phase II Trial Randomizing Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN #1203; Progress I)
Study Start Date : August 2014
Actual Primary Completion Date : October 2017
Actual Study Completion Date : October 2017


Arm Intervention/treatment
Experimental: Tacrolimus/Methotrexate/Bortezomib
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Bortezomib.
Drug: Tacrolimus (ARM with Methotrexate)
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.
Other Names:
  • Prograf®
  • FK506

Drug: Methotrexate (ARM with Bortezomib)
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.
Other Name: MTX

Drug: Bortezomib
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.
Other Name: Velcade®

Experimental: Tacrolimus/Methotrexate/Maraviroc
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Methotrexate, and Maraviroc.
Drug: Tacrolimus (ARM with Methotrexate)
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.
Other Names:
  • Prograf®
  • FK506

Drug: Methotrexate (ARM with Maraviroc)
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.
Other Name: MTX

Drug: Maraviroc
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.
Other Name: Selzentry®

Experimental: Tacrolimus/MMF/Cyclophosphamide
Participants will receive specified dosage of three different GVHD prophylaxis agents: Tacrolimus, Mycophenolate Mofetil (MMF), and Cyclophosphamide.
Drug: Tacrolimus (ARM with MMF and Cyclophosphamide)
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.
Other Names:
  • Prograf®
  • FK506

Drug: Mycophenolate mofetil
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.
Other Name: Cellcept®

Drug: Cyclophosphamide

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).

Other Name: Cytoxan®




Primary Outcome Measures :
  1. GVHD/progression/relapse after Hematopoietic Stem Cell Transplant [ Time Frame: 1 Year ]
    Compare one year GVHD/relapse/progression-free survival after HSCT between each of three novel GVHD prophylaxis approaches and a contemporary control.


Secondary Outcome Measures :
  1. Incidence of Acute GVHD Grades II-IV [ Time Frame: Through 180 days post-HSCT ]
    Cumulative incidences of grade II-IV and III-IV acute GVHD will be determined. Acute GVHD will be graded according to the BMT CTN Manual of Procedures (MOP).

  2. Incidence of Chronic GVHD [ Time Frame: 1 Year ]
    Cumulative incidences of Chronic GVHD will be determined. Chronic GVHD will be graded according to the BMT CTN Manual of Procedures (MOP).

  3. Immunosuppression-free Survival Rate [ Time Frame: 1 Year ]
    Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD.

  4. Hematologic Recovery (Neutrophils and Platelets) [ Time Frame: Through Day 100 post-HSCT ]
    Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm^3 for three consecutive measurements on three different days. Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days.

  5. Donor Cell Engraftment [ Time Frame: Through Day 100 post-HSCT ]
  6. Immune Reconstitution [ Time Frame: 1 Year ]
  7. Disease Relapse or Progression [ Time Frame: 1 Year ]
    Relapse is defined by either morphological evidence of the study disease consistent with pre-transplant features, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy.

  8. Cumulative Incidence of Transplant-Related Mortality [ Time Frame: Up to One Year ]
  9. Frequency of Grade 3 or Greater Toxicities [ Time Frame: 1 Year ]
    All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm.

  10. Incidence of Grade 2 and 3 Infections [ Time Frame: 1 Year ]
    The incidence of definite and probable grade 2 and 3 viral, fungal and bacterial infections will be tabulated for each intervention arm.

  11. Overall Survival(OS) [ Time Frame: 1 Year ]
    OS is defined as the time interval between date of transplant and death from any cause or for surviving patients, to last follow-up. The event for this endpoint is death from any cause.

  12. Disease-free Survival [ Time Frame: 1 Year ]
    Disease-free survival is the time from date of transplant to death or relapse, whichever comes first. The event for this endpoint is relapse or death. Patients alive and free from disease relapse will be censored at last follow-up.

  13. GVHD Survival [ Time Frame: 1 Year ]
    The event for this endpoint includes moderate to severe GVHD according to NIH consensus criteria global score, or death by any cause.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-75 years (patient is older than 18.0 and less than 76.0 years old)
  2. Patients with acute leukemia, chronic myelogenous leukemia or myelodysplasia with no circulating blasts and with less than 5% blasts in the bone marrow.
  3. 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
  4. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a)
  5. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

    1. 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.
    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 be medically cleared to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
  6. Cardiac function: Ejection fraction at rest ≥ 45%
  7. Estimated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight)
  8. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
  9. 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.
  10. 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).
  11. 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.
  12. Signed informed consent

Exclusion Criteria:

  1. Prior allogeneic transplant
  2. Karnofsky Performance Score < 70%
  3. Active central nervous system (CNS) involvement by malignant cells
  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 fluid collection (ascites, pleural or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated
  6. Patients with transformed lymphoma (e.g., Richters transformation arising in follicular lymphoma or chronic lymphocytic leukemia)
  7. Patients seropositive for the human immunodeficiency virus (HIV)
  8. Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification tests (NAAT)
  9. Patients with hypersensitivity to bortezomib, boron or mannitol
  10. Patients with ≥ grade 2 sensory peripheral neuropathy
  11. 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.
  12. Female patients who are lactating or pregnant
  13. Patients with a serious medical or psychiatric illness likely to interfere with participation in this clinical study
  14. 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.
  15. Planned use of anti-thymocyte globulin (ATG) or alemtuzumab in conditioning regimen.
  16. Planned post-transplant therapy, including use of tyrosine-kinase inhibitors (TKI).
  17. Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes (CYP3A4), or glutathione S-transferases involved in bortezomib and/or busulfan metabolism during day -5 through day +7. It is acceptable to use alternative non-interacting medications during this period, and then resume prior medications.
  18. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, including Chronic myelomonocytic leukemia (CMML), with evidence of active myeloproliferative features or myelofibrosis in the background.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02208037


  Show 30 Study Locations
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
Investigators
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT02208037     History of Changes
Other Study ID Numbers: BMTCTN1203
U01HL069294 ( U.S. NIH Grant/Contract )
First Posted: August 4, 2014    Key Record Dates
Last Update Posted: April 6, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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).
Supporting Materials: Study Protocol
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public
URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Acute Lymphoblastic Leukemia/Lymphoma
Acute Myelogenous Leukemia
Mantel-Cell Lymphoma
Hematopoietic Transplant
GVHD Prophylaxis

Additional relevant MeSH terms:
Lymphoma
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid
Hodgkin Disease
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Graft vs Host Disease
Myelodysplastic Syndromes
Preleukemia
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoma, Non-Hodgkin
Cyclophosphamide
Methotrexate
Tacrolimus
Bortezomib
Mycophenolic Acid