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

Sponsor

Case Comprehensive Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01951885

Collaborator

(none)

101

Enrollment

Location

Arms

85.2

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Biphenotypic Leukemia Myelodysplastic Syndrome Myeloproliferative Neoplasm Non-Hodgkin Lymphoma Hodgkins Disease Chronic Lymphocytic Leukemia Multiple Myeloma	Drug: tacrolimus Drug: methotrexate Drug: Mycophenolate mofetil Drug: Methotrexate (low dose)	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

101 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

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

Actual Study Start Date :

Jul 7, 2014

Actual Primary Completion Date :

Oct 9, 2020

Anticipated Study Completion Date :

Aug 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group A (tacrolimus, methotrexate) 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.	Drug: tacrolimus 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 Drug: methotrexate 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
Experimental: Group B (tacrolimus, methotrexate, mycophenolate mofetil) 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).	Drug: tacrolimus 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 Drug: Mycophenolate mofetil 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 Drug: Methotrexate (low dose) 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

Arm

Intervention/Treatment

Active Comparator: Group A (tacrolimus, methotrexate)

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.

Drug: tacrolimus

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

Drug: methotrexate

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

Experimental: Group B (tacrolimus, methotrexate, mycophenolate mofetil)

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).

Drug: tacrolimus

Other Names:

FK 506

Prograf

Drug: Mycophenolate mofetil

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

Drug: Methotrexate (low dose)

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

Outcome Measures

Primary Outcome Measures

Incidence of severe (grade 3-4) mucositis graded according to the World Health Organization (WHO) grading scale [Up to day 28]
Patients will be graded three times per week through day 28 of the study. Incidence will be compared through Wilcoxon rank sum tests.
Time to neutrophil engraftment [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.
Time to platelet engraftment [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.
Incidence of acute GVHD [Day 7- Day 100]
Acute GVHD will be estimated using cumulative incidence methods and compared using the Pepe-Mori test.

Secondary Outcome Measures

Length of hospitalization [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.
Use of total parenteral nutrition (TPN) [Up to day 100]
TPN and 100-day incidence of complications will be compared using the Chi-square test.
Overall survival defined by Center for International Blood and Marrow Transplant Research (CIBMTR) criteria for individual diseases [Up to 1 year]
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Progression-free survival defined by CIBMTR criteria for individual diseases [Up to 1 year]
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Incidence of chronic GVHD [after Day +100, every 3 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.
Length of time on continuous infusion narcotics [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.
Incidence of infection [Up to day +100]
TPN and 100-day incidence of infection will be compared using a Chi-square test. Infection will be monitored up to one year after transplantation
Incidence of hepatotoxicity [Up to day +100]
TPN and 100-day incidence of hepatotoxicity will be compared using a Chi-square test. Hepatotoxicity will be monitored up to one year after transplantation
Incidence of nephrotoxicity [Up to day +100]
TPN and 100-day incidence of nephrotoxicity will be compared using a Chi-square test. Nephrotoxicity will be monitored up to one year after transplantation
Incidence of pulmonary toxicity [Up to day +180]
TPN and 180-day incidence of pulmonary toxicity will be compared using a Chi-square test. Pulmonary toxicity will be monitored up to one year after transplantation

Other Outcome Measures

Chimerism results [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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