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

Primary Purpose

Chronic Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
tacrolimus
methotrexate
Mycophenolate mofetil
Methotrexate (low dose)
Sponsored by
Case Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Chronic Myelogenous Leukemia

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Group A (tacrolimus, methotrexate)

Group B (tacrolimus, methotrexate, mycophenolate mofetil)

Arm Description

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.

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).

Outcomes

Primary Outcome Measures

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
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.
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.
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.

Secondary Outcome Measures

Length of Hospitalization
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
TPN use will be compared using the Chi-square test.
Overall Survival
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Progression-free Survival
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
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
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
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.
Incidence of Infection
100-day incidence of infection will be compared using a the Gray test.
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),
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
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
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
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
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
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

Full Information

First Posted
September 24, 2013
Last Updated
August 16, 2023
Sponsor
Case Comprehensive Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT01951885
Brief Title
Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention
Official Title
Tacrolimus, Mini-dose Methotrexate and Mycophenolate Mofetil Versus Tacrolimus and Methotrexate for the Prevention of Acute Graft-versus-Host-Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
July 7, 2014 (Actual)
Primary Completion Date
October 9, 2020 (Actual)
Study Completion Date
August 11, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Case Comprehensive Cancer Center

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
101 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A (tacrolimus, methotrexate)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Group B (tacrolimus, methotrexate, mycophenolate mofetil)
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Methotrexate (low dose)
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
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.
Primary Outcome Measure Information:
Title
Percentage of Severe (Grade 3-4) Mucositis Graded According to the World Health Organization (WHO) Grading Scale
Description
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 Frame
Up to day 28
Title
Time to Neutrophil Engraftment
Description
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 Frame
Up to 28 days
Title
Time to Platelet Engraftment
Description
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.
Time Frame
The date the participant engrafts, up to 28 days
Title
Cumulative Incidence of Participants With Acute GVHD
Description
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.
Time Frame
Day 7- Day 100
Secondary Outcome Measure Information:
Title
Length of Hospitalization
Description
Hospital stay will be compared between patients in groups A and B using the Wilcoxon rank sum test.
Time Frame
Date of transplant to date of discharge, assessed up to 1 year
Title
Percentage of Participants Using Total Parenteral Nutrition (TPN) Within 100 Days
Description
TPN use will be compared using the Chi-square test.
Time Frame
Up to day 100
Title
Overall Survival
Description
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Time Frame
Up to 1 year
Title
Progression-free Survival
Description
Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Time Frame
Up to 1 year
Title
Incidence of Chronic GVHD
Description
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
Time Frame
at 6 months
Title
Incidence of Chronic GVHD
Description
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
Time Frame
at 12 months
Title
Length of Time on Continuous Infusion Narcotics
Description
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.
Time Frame
up to +28 day
Title
Incidence of Infection
Description
100-day incidence of infection will be compared using a the Gray test.
Time Frame
Up to day +100
Title
Incidence of Hepatotoxicity as Measured by Bilirubin
Description
100-day incidence of hepatotoxicity will be compared using a Gray test. Median and range of largest total bilirubin (mg/dL),
Time Frame
Up to day +100
Title
Incidence of Hepatotoxicity as Measured by Elevated Liver Enzymes
Description
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
Time Frame
Up to day +100
Title
Incidence of Hepatotoxicity as Measured by Veno-occlusive Disease (VOD)
Description
100-day incidence of hepatotoxicity will be compared using the Gray test. Percentage of patients with VOD and 95% confidence interval
Time Frame
Up to day +100
Title
Incidence of Nephrotoxicity
Description
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
Time Frame
Up to day +100
Title
Incidence of Pulmonary Toxicity Measured by Pulmonary Hemorrhage
Description
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary hemorrhage and 95% confidence interval
Time Frame
Up to day +180
Title
Incidence of Pulmonary Toxicity Measured by Pulmonary Edema
Description
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with pulmonary edema and 95% confidence interval
Time Frame
Up to day +180
Title
Incidence of Pulmonary Toxicity Measured by Respiratory Failure
Description
180-day incidence of pulmonary toxicity will be compared using the Gray test. Percentage of patients with respiratory failure and 95% confidence interval
Time Frame
Up to day +180
Other Pre-specified Outcome Measures:
Title
Chimerism Results
Description
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.
Time Frame
Up to one year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Betty Hamilton, MD
Organizational Affiliation
Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States

12. IPD Sharing Statement

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

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