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

Phase 3

Completed

Conditions: Non-Hodgkin Lymphoma
Hodgkins Disease
Acute Biphenotypic Leukemia
Chronic Lymphocytic Leukemia
Chronic Myelogenous Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Myeloproliferative Neoplasm
Acute Lymphoblastic Leukemia
Multiple Myeloma

Interventions: Drug: tacrolimus
Drug: methotrexate
Drug: Mycophenolate mofetil
Drug: Methotrexate (low dose)

Registration Number: NCT01951885

Lead Sponsor: Case Comprehensive Cancer Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 101

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group B (tacrolimus, methotrexate, mycophenolate mofetil)	Methotrexate (low dose)	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).
Group A (tacrolimus, methotrexate)	tacrolimus	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.
Group A (tacrolimus, methotrexate)	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.
Group B (tacrolimus, methotrexate, mycophenolate mofetil)	tacrolimus	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).
Group B (tacrolimus, methotrexate, mycophenolate mofetil)	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).

Primary Outcome Measures

Name	Time	Method
Time to Platelet Engraftment	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.
Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale	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
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.
Cumulative Incidence of Participants With Acute GVHD	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 Outcome Measures

Name	Time	Method
Incidence of Pulmonary Toxicity Measured by Pulmonary Edema	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
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.
Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days	Up to day 100	TPN use will be compared using the Chi-square test.
Progression-free Survival	Up to 1 year	Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Incidence of Hepatotoxicity as Measured by Bilirubin	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),
Overall Survival	Up to 1 year	Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD)	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
Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes	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
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	100-day incidence of infection will be compared using a the Gray test.
Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage	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
Incidence of Pulmonary Toxicity Measured by Respiratory Failure	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
Incidence of Chronic GVHD	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
Incidence of Nephrotoxicity	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