Tacrolimus/Sirolimus/Methotrexate vs Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma

Sponsor
Dana-Farber Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT00928018
Collaborator
Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), National Cancer Institute (NCI) (NIH)
139
Enrollment
5
Locations
2
Arms
65
Duration (Months)
27.8
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This trial is comparing whether using a drug called sirolimus for graft versus host disease (GVHD) prevention can decrease the chance of the participant's lymphoma relapsing after transplantation, compared to using a standard GVHD prevention regimen without sirolimus. Since mTOR inhibitors have anti-lymphoma activity, their use after transplantation may lead to a decreased risk of relapse and hence better transplantation outcome.

Detailed Description

  • Because no one knows which of the study options is best, participants will be "randomized" into one of the two possible groups for GVHD prophylaxis: 1) a sirolimus-containing regimen (tacrolimus, sirolimus and methotrexate) or 2) a sirolimus-free regimen (tacrolimus and methotrexate or cyclosporine and mycophenolate mofetil).

  • Participants will receive a reduced intensity conditioning regimen. This is done to prepare the body for transplantation. This will consist of a combination of drugs (either fludarabine and busulfan or fludarabine, cyclophosphamide and low-dose total body irradiation). The purpose of these drugs is to weaken the immune system and lower the chance of the body rejecting the donated stem cells.

  • Participants will also receive the GVHD prophylaxis regimen that they have been randomized to. These drugs will lower the chance of rejecting the donor cells and lower the chance of developing GVHD.

Study Design

Study Type:
Interventional
Actual Enrollment :
139 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III Multicenter, Randomized Trial Comparing Tacrolimus/Sirolimus/Methotrexate Versus Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma
Study Start Date :
Jun 1, 2009
Actual Primary Completion Date :
Nov 1, 2014
Actual Study Completion Date :
Nov 1, 2014

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: Sirolimus-Containing Regimen

The Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.

Drug: Sirolimus
Taken orally for at least 12 months
Other Names:
  • Rapamycin
  • Drug: Methotrexate
    Given intravenously on the first, third and sixth day after transplant
    Other Names:
  • Abbreviated MTX
  • Trade name:Trexall
  • Drug: Tacrolimus
    Taken orally or given intravenously for at least 6 months
    Other Names:
  • Prograf
  • Active Comparator: Sirolimus-Free regimen

    There are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at a dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at a dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at a dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting on day 3.

    Drug: Methotrexate
    Given intravenously on the first, third and sixth day after transplant
    Other Names:
  • Abbreviated MTX
  • Trade name:Trexall
  • Drug: Tacrolimus
    Taken orally or given intravenously for at least 6 months
    Other Names:
  • Prograf
  • Drug: Cyclosporine
    Taken orally or given intravenously for at least 6 months
    Other Names:
  • Brand names:
  • •Gengraf
  • •Neoral
  • •Sandimmune
  • •Sangcya
  • Drug: MMF
    Taken orally for about 2 months
    Other Names:
  • Mycophenolate mofetil (MMF)
  • Brand Names:
  • CellCept
  • Myfortic
  • Outcome Measures

    Primary Outcome Measures

    1. To Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil [2 years]

    Secondary Outcome Measures

    1. To Compare 2-year Progression-free Survival Between the Two Treatment Arms [2 years]

    2. To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms [2 years]

    3. To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms [6 months]

    4. To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms. [2 years]

    5. To Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied. [2 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 72 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients will be eligible if their primary indication for transplantation is among the following: Indolent B-cell non-Hodgkin lymphoma (NHL); Aggressive B-Cell NHL; T-cell NHL; or Hodgkin Lymphoma.

    • Patients must have one of the following combinations of disease status and disease histology at the time of enrollment: 1) Patients may be transplanted as part of first-line therapy if they have one of the following histologies: CLL with adverse cytogenetics, MCL or, T-cell NHL. 2) Patients may be transplanted as part of treatment for relapsed or refractory disease without a prior autologous transplantation of they have one of the following histologies: Indolent NHL (including CLL/SLL), MCL or T-cell NHL. 3) Patients may be transplanted as part of treatment for disease that has relapsed or progressed after autologous transplantation if they have any of the histologies listed above. Patients may also be enrolled without a prior autologous transplantation if they have a contraindication to autologous transplantation, in the opinion of the treating clinician. 4) There is no minimal or maximal time interval from the patient's last anti-lymphoma therapy and the time of transplantation.

    • 18-72 years of age

    • Matched related or matched unrelated donor

    • Donor willing to donate peripheral blood stem cells and meeting institutional criteria for stem cell donation. The donor must be medically eligible to donate stem cells according to individual transplant center criteria.

    Exclusion Criteria:
    • Patients with Burkitt lymphoma or DLBCL with a c-myc rearrangement

    • Karnofsky performance status of less than 70% at the time of registration

    • Prior allogeneic stem cell transplantation (note that prior autologous stem cell transplantation is allowed)

    • Uncontrolled infection

    • Serum creatinine 2.0mg/dl or greater

    • Total bilirubin 2.0mg/dl or greater (unless related to hemolysis or Gilbert's syndrome)

    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times or greater than the institutional upper limit of normal

    • Left ventricular ejection fraction < 30%

    • Cholesterol > 500mg/dl or triglycerides > 500 mg/dl despite appropriate treatment

    • Seropositivity for HIV

    • Pregnancy or breast-feeding (effective contraception must be used during therapy and for at least 6 months after the end of immunosuppressive agents)

    • Prior history of allergy to sirolimus, tacrolimus, cyclosporine, methotrexate or MMF

    • Concomitant treatment with another investigational drug (unless cleared by study chair)

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Emory University HospitalAtlantaGeorgiaUnited States30322
    2Massachusetts General HospitalBostonMassachusettsUnited States02114
    3Dana-Farber Cancer InstituteBostonMassachusettsUnited States02115
    4University of MinnesotaMinneapolisMinnesotaUnited States55454
    5Ohio State UniversityColumbusOhioUnited States43210

    Sponsors and Collaborators

    • Dana-Farber Cancer Institute
    • Brigham and Women's Hospital
    • Massachusetts General Hospital
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Philippe Armand, MD, PhD, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Philippe Armand, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00928018
    Other Study ID Numbers:
    • 09-073
    • CA142106
    First Posted:
    Jun 25, 2009
    Last Update Posted:
    Feb 1, 2019
    Last Verified:
    Jan 1, 2019
    Keywords provided by Philippe Armand, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Period Title: Overall Study
    STARTED6673
    COMPLETED6573
    NOT COMPLETED10

    Baseline Characteristics

    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free RegimenTotal
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 monthsTotal of all reporting groups
    Overall Participants6673139
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    58
    57
    57
    Sex: Female, Male (Count of Participants)
    Female
    24
    36.4%
    29
    39.7%
    53
    38.1%
    Male
    42
    63.6%
    44
    60.3%
    86
    61.9%
    Region of Enrollment (participants) [Number]
    United States
    66
    100%
    73
    100%
    139
    100%

    Outcome Measures

    1. Primary Outcome
    TitleTo Compare 2-year Overall Survival of Patients With Lymphoma Undergoing RIC SCT Between Those Receiving Tacrolimus/Sirolimus/Methotrexate and Those Receiving Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Measure Participants6673
    Number (95% Confidence Interval) [percentage of participants]
    70
    106.1%
    68
    93.2%
    2. Secondary Outcome
    TitleTo Compare 2-year Progression-free Survival Between the Two Treatment Arms
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Measure Participants6673
    Number (95% Confidence Interval) [percentage of participants]
    61
    92.4%
    58
    79.5%
    3. Secondary Outcome
    TitleTo Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Measure Participants6673
    Cumulative incidence of relapse/progression
    26
    39.4%
    30
    41.1%
    Non-relapse mortality
    14
    21.2%
    12
    16.4%
    4. Secondary Outcome
    TitleTo Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms
    Description
    Time Frame6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Measure Participants6673
    Grade II-IV aGVHD
    9
    13.6%
    25
    34.2%
    Grade III-IV aGVHD
    3
    4.5%
    4
    5.5%
    5. Secondary Outcome
    TitleTo Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms.
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    Measure Participants6673
    Number [percentage of participants]
    59
    89.4%
    63
    86.3%
    6. Secondary Outcome
    TitleTo Compare the 2-year of Overall Survival, Progression-free Survival, Cumulative Incidences of Progression and Non-relapse Mortality Between the Treatment Arms for Each Histology Studied.
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    Given the small number of patients within each group, we considered indolent histologies (indolent B-cell NHL, CLL and HL) together in one group (indolent group), and aggressive histologies (aggressive B-cell NHL, MCL, and T-cell NHL) in another (aggressive group).
    Arm/Group TitleIndolent Group: Sirolimus-Containing RegimenIndolent Group: Sirolimus-Free RegimenAggressive Group: Sirolimus-Containing RegimenAggressive Group: Sirolimus-Free Regimen
    Arm/Group DescriptionIndolent group:indolent B-cell NHL, CLL and HL histologies The Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3.Taken orally or given intravenously for at least 6 months Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2.Taken orally for at least 12 months Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.Given intravenously on the first, third and sixth day after transplantIndolent group: indolent B-cell NHL, CLL and HL histologies There are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Taken orally or given intravenously for at least 6 months Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. Taken orally or given intravenously for at least 6 months MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Taken orally for about 2 months.Aggressive group: aggressive B-cell NHL, MCL, and T-cell NHL histologies The Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3.Taken orally or given intravenously for at least 6 months Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2.Taken orally for at least 12 months Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6.Given intravenously on the first, third and sixth day after transplantAggressive group: aggressive B-cell NHL, MCL, and T-cell NHL histologies There are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Taken orally or given intravenously for at least 6 months Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. Taken orally or given intravenously for at least 6 months MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Taken orally for about 2 months.
    Measure Participants38402833
    Overall Survival
    82
    124.2%
    63
    86.3%
    54
    38.8%
    76
    NaN
    Progression Free Survival
    71
    107.6%
    53
    72.6%
    46
    33.1%
    64
    NaN
    Cumulative Incidence of Progression
    21
    31.8%
    33
    45.2%
    32
    23%
    27
    NaN
    Non-relapse mortality
    8
    12.1%
    15
    20.5%
    21
    15.1%
    9
    NaN

    Adverse Events

    Time FrameParticipating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during the study. The study defined follow up period is 2 years.
    Adverse Event Reporting Description All AEs grades 3-5 and SAEs whether reported by participant, discovered during questioning, directly observed, or detected by physical examination, laboratory test, etc, will be recorded in participant's medical record and appropriate study-specific forms Only events reported in >1 patient on at least one of the arms are listed in Other AE table
    Arm/Group TitleSirolimus-Containing RegimenSirolimus-Free Regimen
    Arm/Group DescriptionThe Sirolimus containing arm will consist of the following drugs: Experimental Arm: tacrolimus + sirolimus + low-dose methotrexate Tacrolimus: Administered orally at a dose of 0.05 mg/kg based on ABW bid starting on day -3. Sirolimus:Given as a loading oral dose of 12 mg on day -3, then as a daily maintenance dose of 4 mg starting on day -2. Methotrexate: Administered by intravenous bolus infusion, per institutional standard, at a dose of 5 mg/m2 on days +1, +3 and +6. Sirolimus: Taken orally for at least 12 months Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 monthsThere are two choices for the Sirolimus free arm: Control Arm 1: tacrolimus + methotrexate Tacrolimus:Administered orally at dose of 0.05 mg/kg based on ABW bid starting on day -3. Methotrexate:Administered by intravenous bolus infusion at dose of 5 mg/m2 on days +1, +3 and +6. For patients receiving stem cells from unrelated donors, an additional dose will be given on day +11. Control Arm 2: cyclosporine + MMF Cyclosporine: administered orally at dose of 6 mg/kg based on ABW bid starting on day -3. MMF:administered at dose of 3gm daily orally (or intravenously if the patient cannot tolerate oral administration) divided in 2 or 3 doses (bid or tid) depending on physician preference starting day 3. Methotrexate: Given intravenously on the first, third and sixth day after transplant Tacrolimus: Taken orally or given intravenously for at least 6 months Cyclosporine: Taken orally or given intravenously for at least 6 months MMF: Taken orally for about 2 months
    All Cause Mortality
    Sirolimus-Containing RegimenSirolimus-Free Regimen
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN)
    Serious Adverse Events
    Sirolimus-Containing RegimenSirolimus-Free Regimen
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total15/66 (22.7%) 15/73 (20.5%)
    Blood and lymphatic system disorders
    Hemolysis0/66 (0%) 01/73 (1.4%) 1
    Thrombotic Microangiopathy0/66 (0%) 01/73 (1.4%) 1
    Cardiac disorders
    Pericardial Effusion0/66 (0%) 01/73 (1.4%) 1
    Heart Failure0/66 (0%) 01/73 (1.4%) 1
    Supraventricular and Nodal Arrhythmia0/66 (0%) 01/73 (1.4%) 1
    Gastrointestinal disorders
    Ascites1/66 (1.5%) 11/73 (1.4%) 1
    Obstuction--GI, small bowel1/66 (1.5%) 10/73 (0%) 0
    Gastrointestinal pain1/66 (1.5%) 10/73 (0%) 0
    General disorders
    Edema0/66 (0%) 01/73 (1.4%) 1
    Multi-organ failure0/66 (0%) 01/73 (1.4%) 1
    Hepatobiliary disorders
    Liver failure1/66 (1.5%) 10/73 (0%) 0
    Immune system disorders
    GVHD0/66 (0%) 04/73 (5.5%) 4
    Other- Systemic inflammatory response syndrome (SIRS)0/66 (0%) 01/73 (1.4%) 1
    Infections and infestations
    Infection8/66 (12.1%) 116/73 (8.2%) 6
    Investigations
    Leukopenia0/66 (0%) 01/73 (1.4%) 1
    Thrombocytopenia2/66 (3%) 20/73 (0%) 0
    Musculoskeletal and connective tissue disorders
    Fracture1/66 (1.5%) 10/73 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other: Relapse/Progressive disease2/66 (3%) 23/73 (4.1%) 3
    Treatment Related Secondary Malignancy1/66 (1.5%) 10/73 (0%) 0
    Nervous system disorders
    Encephalopathy1/66 (1.5%) 10/73 (0%) 0
    Seizure0/66 (0%) 01/73 (1.4%) 1
    Altered mental status0/66 (0%) 02/73 (2.7%) 2
    Memory impairment0/66 (0%) 01/73 (1.4%) 1
    Hemorrhage, CNS (cerebrovascular)0/66 (0%) 01/73 (1.4%) 1
    Confusion0/66 (0%) 02/73 (2.7%) 2
    Renal and urinary disorders
    Acute Kidney Injury/Renal Failure3/66 (4.5%) 31/73 (1.4%) 1
    Respiratory, thoracic and mediastinal disorders
    Adult Respiratory Distress Syndrome (ARDS)1/66 (1.5%) 10/73 (0%) 0
    Aspiration0/66 (0%) 01/73 (1.4%) 1
    Dyspnea0/66 (0%) 01/73 (1.4%) 1
    Hypoxia3/66 (4.5%) 31/73 (1.4%) 1
    Other--Respiratory failure/lung injury2/66 (3%) 20/73 (0%) 0
    Pulmonary hemorrhage1/66 (1.5%) 10/73 (0%) 0
    Vascular disorders
    Other--Stroke1/66 (1.5%) 10/73 (0%) 0
    Pulmonary embolism2/66 (3%) 22/73 (2.7%) 2
    Other (Not Including Serious) Adverse Events
    Sirolimus-Containing RegimenSirolimus-Free Regimen
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total41/66 (62.1%) 54/73 (74%)
    Blood and lymphatic system disorders
    Neutropenia12/66 (18.2%) 1216/73 (21.9%) 16
    Cardiac disorders
    Cardiac3/66 (4.5%) 37/73 (9.6%) 7
    Hypotension1/66 (1.5%) 12/73 (2.7%) 2
    Eye disorders
    Cataract2/66 (3%) 21/73 (1.4%) 1
    Gastrointestinal disorders
    Anorexia2/66 (3%) 21/73 (1.4%) 1
    Diarrhea3/66 (4.5%) 34/73 (5.5%) 4
    Stomatitis/mucositis1/66 (1.5%) 14/73 (5.5%) 4
    Nausea/vomiting4/66 (6.1%) 41/73 (1.4%) 1
    Abdominal pain1/66 (1.5%) 15/73 (6.8%) 5
    Hepatobiliary disorders
    Hepatic4/66 (6.1%) 415/73 (20.5%) 15
    Immune system disorders
    Allergic Reaction0/66 (0%) 02/73 (2.7%) 2
    Infections and infestations
    Infection3/66 (4.5%) 317/73 (23.3%) 17
    Investigations
    Thrombocytopenia11/66 (16.7%) 1114/73 (19.2%) 14
    Leukopenia6/66 (9.1%) 68/73 (11%) 8
    Metabolism and nutrition disorders
    Hyperlipidemia2/66 (3%) 22/73 (2.7%) 2
    Hyperglycemia3/66 (4.5%) 33/73 (4.1%) 3
    Dehydration1/66 (1.5%) 12/73 (2.7%) 2
    Hyponatremia1/66 (1.5%) 12/73 (2.7%) 2
    Musculoskeletal and connective tissue disorders
    Weakness3/66 (4.5%) 31/73 (1.4%) 1
    Nervous system disorders
    Confusion/psychosis/encephalopathy8/66 (12.1%) 84/73 (5.5%) 4
    Neuropathy4/66 (6.1%) 40/73 (0%) 0
    Pain1/66 (1.5%) 18/73 (11%) 8
    Renal and urinary disorders
    TMA/renal failure/hemolysis12/66 (18.2%) 126/73 (8.2%) 6
    Respiratory, thoracic and mediastinal disorders
    Respiratory2/66 (3%) 210/73 (13.7%) 10
    Skin and subcutaneous tissue disorders
    Rash1/66 (1.5%) 14/73 (5.5%) 4
    Vascular disorders
    Hematoma2/66 (3%) 21/73 (1.4%) 1
    Thrombosis1/66 (1.5%) 18/73 (11%) 8

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitlePhilippe Armand, MD, PhD
    OrganizationDana Farber Cancer Institute
    Phone617-632-2305
    Emailparmand@partners.org
    Responsible Party:
    Philippe Armand, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00928018
    Other Study ID Numbers:
    • 09-073
    • CA142106
    First Posted:
    Jun 25, 2009
    Last Update Posted:
    Feb 1, 2019
    Last Verified:
    Jan 1, 2019