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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Multiple Myeloma; Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; Myelodysplastic Syndrome; Chronic Myelogenous Leukemia; Myeloproliferative Neoplasm; Acute Biphenotypic Leukemia; Hodgkins Disease
• Intervention / Treatment: Drug: tacrolimus; Drug: methotrexate; Drug: Mycophenolate mofetil; Drug: Methotrexate (low dose)

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 Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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: Prograf; FK 506; 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: Prograf; FK 506; 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

What is the study measuring?

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
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
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

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
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 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 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
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 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 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chimerism Results	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.	Up to one year

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Investigators: Principal Investigator: Betty Hamilton, MD, Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2014
• Primary Completion (Actual): October 9, 2020
• Study Completion (Actual): August 11, 2021

Study Registration Dates

• First Submitted: September 24, 2013
• First Submitted That Met QC Criteria: September 24, 2013
• First Posted (Estimated): September 27, 2013

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Chronic Disease; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Hodgkin Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Antitubercular Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methotrexate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: CASE6Z13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No