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NCT01951885 · REGISTRY CONDITION SEARCH

Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2023-09-11

This randomized clinical trial studies standard GVHD prophylaxis with tacrolimus and methotrexate compared to tacrolimus, mycophenolate mofetil and a reduced-dose methotrexate in patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant. Both mycophenolate mofetil and reduced-dose methotrexate, in combination with a calcineurin inhibitor, have been shown to be safe and effective in GVHD prevention with less toxicity than standard dose methotrexate. It is not yet known, however, whether this combination of mycophenolate mofetil and reduced-dose methotrexate with tacrolimus is more effective than tacrolimus and standard dose methotrexate in preventing GVHD.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale

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outcome · POSTED

Time to Neutrophil Engraftment

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outcome · POSTED

Time to Platelet Engraftment

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outcome · POSTED

Cumulative Incidence of Participants With Acute GVHD

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outcome · POSTED

Length of Hospitalization

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outcome · POSTED

Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days

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outcome · POSTED

Overall Survival

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outcome · POSTED

Progression-free Survival

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outcome · POSTED

Incidence of Chronic GVHD

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outcome · POSTED

Incidence of Chronic GVHD

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outcome · POSTED

Length of Time on Continuous Infusion Narcotics

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outcome · POSTED

Incidence of Infection

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outcome · POSTED

Incidence of Hepatotoxicity as Measured by Bilirubin

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outcome · POSTED

Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes

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outcome · POSTED

Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD)

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outcome · POSTED

Incidence of Nephrotoxicity

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outcome · POSTED

Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage

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outcome · POSTED

Incidence of Pulmonary Toxicity Measured by Pulmonary Edema

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outcome · POSTED

Incidence of Pulmonary Toxicity Measured by Respiratory Failure

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outcome · NOT POSTED

Chimerism Results

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Patients must have one of the following documented diseases: * Chronic myelogenous leukemia * Chronic lymphocytic leukemia * Multiple myeloma * Myelodysplasia * Myeloproliferative disorder * Non-Hodgkin's lymphoma * Hodgkin's disease * Acute myelogenous leukemia * Acute lymphoblastic leukemia * Acute biphenotypic leukemia * Patients must be undergoing a myeloablative allogeneic hematopoietic cell transplant with one of the following conditioning regimens: * Busulfan (≥ 12.8 mg/kg IV or PO) and cyclophosphamide (≥ 120 mg/kg) \--- Busulfan dose may be adjusted according to pharmacokinetics targeting a daily AUC of 5000 μmol-min/L, per institution standard of practice. * Total body irradiation (TBI) (≥ 1200 cGy) and etoposide (60 mg/kg) * TBI (≥ 1200 cGy) and cyclophosphamide (120 mg/kg) * Patient must have achieved and be in complete morphologic remission prior to starting conditioning regimen * Patient's donor must be a related or unrelated human leukocyte antigen (HLA) 8/8 allele-level match (HLA-A, B, C and DRB1) * Adult patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; pediatric patients must have Lansky score ≥ 60% * Patients must have a life expectancy of 100 days * Patients must sign written informed consent Exclusion Criteria: * Patients who have undergone any prior transplant * Patients who are seropositive for human immunodeficiency virus (HIV) * Patients with any medical illness or concurrent psychiatric illness which, in the investigators' opinion, cannot be adequately controlled with appropriate therapy * Patients who are pregnant or lactating
healthy Volunteers
false
maximum Age
70 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
  3. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Participants receive tacrolimus IV over 24 hours beginning on day -1 (or tacrolimus orally beginning on day -3) and then PO BID after engraftment with a taper from day 100 to day 180 (in the absence of GVHD). Patients also receive methotrexate IV on days 1, 3, 6, and 11.
    intervention Names
    1. Drug: tacrolimus
    2. Drug: methotrexate
    label
    Group A (tacrolimus, methotrexate)
    type
    ACTIVE_COMPARATOR
  2. description
    Patients receive tacrolimus as in group A and methotrexate (low dose) IV on days 1, 3, and 6. Patients also receive oral mycophenolate mofetil BID beginning on day 1, with a taper from day 45 to day 100 (in the absence of GVHD).
    intervention Names
    1. Drug: tacrolimus
    2. Drug: Mycophenolate mofetil
    3. Drug: Methotrexate (low dose)
    label
    Group B (tacrolimus, methotrexate, mycophenolate mofetil)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Group A (tacrolimus, methotrexate)
    2. Group B (tacrolimus, methotrexate, mycophenolate mofetil)
    description
    Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL
    name
    tacrolimus
    other Names
    1. FK 506
    2. Prograf
    type
    DRUG
  2. arm Group Labels
    1. Group A (tacrolimus, methotrexate)
    description
    MTX 15mg/m2 IV on day +1, followed by 10mg/m2 on day +3, +6, +11. If patient \< 10 kg then MTX will be given at 0.5 mg/kg IV on day +1. Then MTX will be given at 0.33 mg/kg on days +3, +6 and +11.
    name
    methotrexate
    other Names
    1. amethopterin
    2. Folex
    3. methylaminopterin
    4. Mexate
    5. MTX
    type
    DRUG
  3. arm Group Labels
    1. Group B (tacrolimus, methotrexate, mycophenolate mofetil)
    description
    Patients will receive Mycophenolate beginning on day +1. Patients \>40 kg will receive Mycophenolate 1000 mg twice a day. Mycophenolate should be given orally twice a day. IV formulation may be used if the patient cannot tolerate oral route. Patients \< 40 kg will receive MMF 45 mg/kg/day (15 mg/kg three times a day). MMF may be given orally or intravenously as per institutional protocol
    name
    Mycophenolate mofetil
    other Names
    1. Cellcept
    2. MMF
    type
    DRUG
  4. arm Group Labels
    1. Group B (tacrolimus, methotrexate, mycophenolate mofetil)
    description
    MTX 5mg/m2 IV on day +1, +3, +6. If patient\<10 kg MTX will be given at 0.17 mg/kg on day +1, +3, and +6.
    name
    Methotrexate (low dose)
    other Names
    1. amethopterin
    2. Folex
    3. methylaminopterin
    4. Mexate
    5. MTX
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
SUPPORTIVE_CARE
Enrollment
count
101
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    Donor chimerism will be assessed by analysis of single-tandem repeats on whole marrow and in lymphocyte enriched or sorted CD3+ T cells and CD33+ granulocytes. Blood will be obtained for donor chimerism "Bone Marrow Engraftment analysis" at approximately 1, 2, 3, 6, 9 and 12 months or as clinically indicated.
    measure
    Chimerism Results
    time Frame
    Up to one year
primary Outcomes
  1. description
    Participants (percentage of) will be graded three times per week through day 28 of the study. Incidence will be compared through Wilcoxon rank sum tests. The WHO grading scale for mucositis is scaled depending on the severity of mucositis symptoms, with a lower stage associated with a better outcome and greater stages associated with worse outcomes. The staging is as follows: Stage 0: None Stage 1 (mild): Oral soreness, erythema Stage 2 (moderate): Oral erythema, ulcers, solid diet tolerated Stage 3 (severe): Oral ulcers, liquid diet only Stage 4 (life-threatening): Oral alimentation impossible
    measure
    Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale
    time Frame
    Up to day 28
  2. description
    The number of days to reach a neutrophil count of greater than or equal to 500/ul for three consecutive laboratory values obtained on different days. The day of engraftment will be the first day of the three consecutive laboratory values.
    measure
    Time to Neutrophil Engraftment
    time Frame
    Up to 28 days
  3. description
    The number of days to reach a platelet count of greater than or equal to 20,000/ul for three consecutive laboratory values obtained on different days, independent of platelet transfusions the prior 7 days. The day of engraftment will be the first day of the three consecutive laboratory values. For cases of delayed engraftment beyond 28 days, results will be recorded once the participant engrafts.
    measure
    Time to Platelet Engraftment
    time Frame
    The date the participant engrafts, up to 28 days
  4. description
    Acute GVHD by grade will be estimated using cumulative incidence methods and compared using the Gray test. A lower clinical grade and/or stage of GVHD corresponds to a better participant outcome and a higher grade corresponds to a worse participant outcome. Grading is as follows: Grade 0: No stage 1-4 of any organ Grade 1: Stage 1-2 skin without liver, upper GI, or lower GI involvement. Grade 2: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. Grade 3: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. Grade 4: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. A greater stage of GVHD involves worsening end-organ involvement and worse participant outcomes based on the skin, liver, lower GI, and upper GI.
    measure
    Cumulative Incidence of Participants With Acute GVHD
    time Frame
    Day 7- Day 100
secondary Outcomes
  1. description
    Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test.
    measure
    Length of Hospitalization
    time Frame
    Date of transplant to date of discharge, assessed up to 1 year
  2. description
    TPN use will be compared using the Chi-square test.
    measure
    Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days
    time Frame
    Up to day 100
  3. description
    Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
    measure
    Overall Survival
    time Frame
    Up to 1 year
  4. description
    Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
    measure
    Progression-free Survival
    time Frame
    Up to 1 year
  5. description
    Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of 3 OR Lung score of 2 or 3 Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes. Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
    measure
    Incidence of Chronic GVHD
    time Frame
    at 6 months
  6. description
    Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. The type and duration of immunosuppressive treatment given for cGVHD will be recorded. Mild grades are associated with a better participant outcome and severe corresponds to a worse participant outcome. Grading is as follows: Mild: 1 or 2 organs involved with no more than score 1 plus Lung score 0 Moderate: 3 or more organs involved with no more than score 1 OR At least 1 organ (not lung) with a score of 2 OR Lung score 1 Severe: At least 1 organ with a score of 3 OR Lung score of 2 or 3 Organ scores can range from 0 to 3, with 0 being no symptoms on the target organ and a better participant outcome while a score of 3 correlates to severe symptoms on the target organ and worse participant outcomes. Potential target organs include: skin, mouth, eyes, GI tract, liver, lungs, joint /fascia, and genital tract
    measure
    Incidence of Chronic GVHD
    time Frame
    at 12 months
  7. description
    Start and stop dates for the need of continuous IV infusion of narcotics for severe mucositis pain will be recorded. Time on IV infusion will be compared between patients in groups A and B using the Wilcoxon rank sum test.
    measure
    Length of Time on Continuous Infusion Narcotics
    time Frame
    up to +28 day
  8. description
    100-day incidence of infection will be compared using a the Gray test.
    measure
    Incidence of Infection
    time Frame
    Up to day +100
  9. description
    100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL),
    measure
    Incidence of Hepatotoxicity as Measured by Bilirubin
    time Frame
    Up to day +100
  10. description
    100-day incidence of hepatotoxicity will be compared using a Gray test. Percentage of patients with elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and alkaline phosphatase and a 95% confidence interval
    measure
    Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes
    time Frame
    Up to day +100
  11. description
    100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval
    measure
    Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD)
    time Frame
    Up to day +100
  12. description
    100-day incidence of nephrotoxicity will be compared using a Chi-squared test. Percentage of patients requiring dialysis and those with elevated creatinine using a 95% confidence interval
    measure
    Incidence of Nephrotoxicity
    time Frame
    Up to day +100
Full study description
brief Summary
This randomized clinical trial studies standard GVHD prophylaxis with tacrolimus and methotrexate compared to tacrolimus, mycophenolate mofetil and a reduced-dose methotrexate in patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant. Both mycophenolate mofetil and reduced-dose methotrexate, in combination with a calcineurin inhibitor, have been shown to be safe and effective in GVHD prevention with less toxicity than standard dose methotrexate. It is not yet known, however, whether this combination of mycophenolate mofetil and reduced-dose methotrexate with tacrolimus is more effective than tacrolimus and standard dose methotrexate in preventing GVHD.
detailed Description
Study Design This is a prospective randomized trial to determine the effectiveness of different doses of GVHD prophylaxis on mucositis, engraftment and aGVHD. Study consists of two study groups of 50 subjects each. Group A will receive Tac and MTX (15 mg/m2 day +1, 10 mg/m2 day +3, +6, +11). Group B will receive Tac, Mini-dose MTX (5 mg/m2 on day +1, +3, +6) and MMF.
Source references
references
  1. citation
    Hamilton BK, Rybicki LA, Li H, Lucas T, Corrigan D, Kalaycio M, Sobecks R, Hanna R, Rotz SJ, Dean RM, Gerds AT, Jagadeesh D, Brunstein C, Sauter CS, Copelan EA, Majhail NS. Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention. Blood Adv. 2023 Aug 22;7(16):4505-4513. doi: 10.1182/bloodadvances.2023010310.
    pmid
    37352262
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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    Preserved source evidence · Not medical advice