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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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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

Intervention / Treatment
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* Drug: tacrolimus
* Drug: methotrexate
* Drug: Mycophenolate mofetil
* Drug: Methotrexate (low dose)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A (tacrolimus, methotrexate)<br>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<br>* 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<br>* Other names: Prograf;Drug: methotrexate<br>* 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.<br>* Other names: MTX;|
| Experimental: Group B (tacrolimus, methotrexate, mycophenolate mofetil)<br>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<br>* 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<br>* Other names: Prograf;Drug: Mycophenolate mofetil<br>* 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<br>* Other names: MMF;Drug: Methotrexate (low dose)<br>* 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.<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale | 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 | Up to day 28 | 
| Time to Neutrophil Engraftment | 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. | Up to 28 days | 
| Time to Platelet Engraftment | 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. | The date the participant engrafts, up to 28 days | 
| Cumulative Incidence of Participants With Acute GVHD | 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. | Day 7- Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of Hospitalization | Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test. | Date of transplant to date of discharge, assessed up to 1 year | 
| Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days | TPN use will be compared using the Chi-square test. | Up to day 100 | 
| Overall Survival | Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. | Up to 1 year | 
| Progression-free Survival | Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test. | Up to 1 year | 
| Incidence of Chronic GVHD | 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 | at 6 months | 
| Incidence of Chronic GVHD | 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 | at 12 months | 
| Length of Time on Continuous Infusion Narcotics | 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. | up to +28 day | 
| Incidence of Infection | 100-day incidence of infection will be compared using a the Gray test. | Up to day +100 | 
| Incidence of Hepatotoxicity as Measured by Bilirubin | 100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL), | Up to day +100 | 
| Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes | 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 | Up to day +100 | 
| Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD) | 100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval | Up to day +100 | 
| Incidence of Nephrotoxicity | 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 | Up to day +100 | 
| Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval | Up to day +180 | 
| Incidence of Pulmonary Toxicity Measured by Pulmonary Edema | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval | Up to day +180 | 
| Incidence of Pulmonary Toxicity Measured by Respiratory Failure | 180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval | Up to day +180 |