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NCT Number: NCT01951885

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

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.

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Key information

Conditions

Chronic Myelogenous Leukemia Acute Biphenotypic Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Blood Protein Disorders Bone Marrow Diseases Cardiovascular Diseases Chronic Disease Chronic Lymphocytic Leukemia Disease Attributes Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders Hemostatic Disorders Hodgkin Disease Hodgkins Disease Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, B-Cell Leukemia, Biphenotypic, Acute Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid Leukemia, Myeloid, Acute Lymphatic Diseases Lymphoma Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Multiple Myeloma Myelodysplastic Syndrome Myelodysplastic Syndromes Myeloproliferative Disorders Myeloproliferative Neoplasm Neoplasms Neoplasms by Histologic Type Neoplasms, Plasma Cell Non-Hodgkin Lymphoma Paraproteinemias Pathologic Processes Pathological Conditions, Signs and Symptoms Precursor Cell Lymphoblastic Leukemia-Lymphoma Vascular Diseases

Age range

Up to 70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Tacrolimus

Drug

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

Other names: FK 506, Prograf

methotrexate

Drug

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.

Other names: amethopterin, Folex, methylaminopterin, Mexate, MTX

Mycophenolate mofetil

Drug

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

Other names: Cellcept, MMF

Methotrexate (low dose)

Drug

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.

Other names: amethopterin, Folex, methylaminopterin, Mexate, MTX

Primary outcomes

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

    Time frame: Up to day 28

    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

  2. Time to Neutrophil Engraftment

    Time frame: Up to 28 days

    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.

  3. Time to Platelet Engraftment

    Time frame: The date the participant engrafts, up to 28 days

    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.

  4. Cumulative Incidence of Participants With Acute GVHD

    Time frame: Day 7- Day 100

    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.

Secondary outcomes

  1. Length of Hospitalization

    Time frame: Date of transplant to date of discharge, assessed up to 1 year

    Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test.

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

    Time frame: Up to day 100

    TPN use will be compared using the Chi-square test.

  3. Overall Survival

    Time frame: Up to 1 year

    Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.

  4. Progression-free Survival

    Time frame: Up to 1 year

    Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.

  5. Incidence of Chronic GVHD

    Time frame: at 6 months

    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

  6. Incidence of Chronic GVHD

    Time frame: at 12 months

    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

  7. Length of Time on Continuous Infusion Narcotics

    Time frame: up to +28 day

    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.

  8. Incidence of Infection

    Time frame: Up to day +100

    100-day incidence of infection will be compared using a the Gray test.

  9. Incidence of Hepatotoxicity as Measured by Bilirubin

    Time frame: Up to day +100

    100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL),

  10. Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes

    Time frame: Up to day +100

    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

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

    Time frame: Up to day +100

    100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval

  12. Incidence of Nephrotoxicity

    Time frame: Up to day +100

    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

  13. Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage

    Time frame: Up to day +180

    180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval

  14. Incidence of Pulmonary Toxicity Measured by Pulmonary Edema

    Time frame: Up to day +180

    180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval

  15. Incidence of Pulmonary Toxicity Measured by Respiratory Failure

    Time frame: Up to day +180

    180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval

Other outcomes

  1. Chimerism Results

    Time frame: Up to one year

    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.

Sponsors and collaborators

Lead sponsor

Case Comprehensive Cancer Center

Other

Registry information

Official study title

Tacrolimus, Mini-dose Methotrexate and Mycophenolate Mofetil Versus Tacrolimus and Methotrexate for the Prevention of Acute Graft-versus-Host-Disease

Important dates

Study start
2014
Primary completion
2020
Study completion
2021
First posted
Sep 27, 2013
Registry last updated
Sep 11, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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