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

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ClinicalTrials.gov Identifier: NCT01951885
Recruitment Status : Recruiting
First Posted : September 27, 2013
Last Update Posted : June 19, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE September 24, 2013
First Posted Date  ICMJE September 27, 2013
Last Update Posted Date June 19, 2019
Actual Study Start Date  ICMJE May 21, 2014
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 11, 2013)
  • Incidence of severe (grade 3-4) mucositis graded according to the World Health Organization (WHO) grading scale [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Day 7- Day 100 ]
    Acute GVHD will be estimated using cumulative incidence methods and compared using the Pepe-Mori test.
Original Primary Outcome Measures  ICMJE
 (submitted: September 24, 2013)
  • Incidence of severe (grade 3-4) mucositis graded according to the World Health Organization (WHO) grading scale [ Time Frame: Up to day 28 ]
  • Time to neutrophil engraftment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to day 100 ]
    Acute GVHD will be estimated using cumulative incidence methods and compared using the Pepe-Mori test.
  • Incidence of chronic GVHD [ Time Frame: Up to 1 year ]
    Chronic GVHD will be graded as mild, moderate, or severe based on the National Institutes of Health Consensus Development Project. It will be estimated using cumulative incidence methods and compared using the Pepe-Mori test.
Change History Complete list of historical versions of study NCT01951885 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 11, 2013)
  • Length of hospitalization [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2013)
  • Length of hospitalization [ Time Frame: Date of transplant to date of discharge, assessed up to 1 year ]
    Hospital stay will be compared between groups using the Wilcoxon rank sum test.
  • Use of total parenteral nutrition (TPN) [ Time Frame: Up to day 100 ]
    TPN and 100-day incidence of complications will be compared using the Chi-square test.
  • Incidence of complications [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to 1 year ]
    Estimated using the Kaplan-Meier method and compared between the 2 groups using the log-rank test.
Current Other Pre-specified Outcome Measures
 (submitted: October 11, 2013)
Chimerism results [ Time Frame: 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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention
Official Title  ICMJE Tacrolimus, Mini-dose Methotrexate and Mycophenolate Mofetil Versus Tacrolimus and Methotrexate for the Prevention of Acute Graft-versus-Host-Disease
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE
  • 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  ICMJE
  • Drug: tacrolimus
    Tacrolimus 0.03 mg/kg/day beginning day -1. Tac will be administered IV over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and 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
  • 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
Study Arms  ICMJE
  • Active Comparator: Group A (tacrolimus, methotrexate)
    Patients receive tacrolimus IV over 24 hours beginning on day -1 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.
    Interventions:
    • Drug: tacrolimus
    • Drug: methotrexate
  • 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).
    Interventions:
    • Drug: tacrolimus
    • Drug: Mycophenolate mofetil
    • Drug: Methotrexate (low dose)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 24, 2013)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01951885
Other Study ID Numbers  ICMJE CASE6Z13
NCI-2013-01800 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CASE 6Z13 ( Other Identifier: Case Comprehensive Cancer Center )
P30CA043703 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Case Comprehensive Cancer Center
Study Sponsor  ICMJE Case Comprehensive Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Betty Hamilton, MD Case Comprehensive Cancer Center
PRS Account Case Comprehensive Cancer Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP