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

Primary Purpose

Non-hodgkin Lymphoma, Hodgkin Lymphoma

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Sirolimus

Methotrexate

Tacrolimus

Cyclosporine

MMF

About this trial

This is an interventional treatment trial for Non-hodgkin Lymphoma focused on measuring allogeneic stem cell transplant, reduced intensity conditioning, graft versus host disease, GVHD, RIC transplantation

Eligibility Criteria

18 Years - 72 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Emory University Hospital
Massachusetts General Hospital
Dana-Farber Cancer Institute
University of Minnesota
Ohio State University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Sirolimus-Containing Regimen

Sirolimus-Free regimen

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

To Compare 2-year Progression-free Survival Between the Two Treatment Arms

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

To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms

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

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.

Full Information

NCT ID

NCT00928018

First Posted

June 24, 2009

Last Updated

January 30, 2019

Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital, National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00928018

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

January 2019

Overall Recruitment Status

Completed

Study Start Date

June 2009 (undefined)

Primary Completion Date

November 2014 (Actual)

Study Completion Date

November 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital, National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

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

Non-hodgkin Lymphoma, Hodgkin Lymphoma

Keywords

allogeneic stem cell transplant, reduced intensity conditioning, graft versus host disease, GVHD, RIC transplantation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

139 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sirolimus-Containing Regimen

Arm Type

Active Comparator

Arm Description

Arm Title

Sirolimus-Free regimen

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

Rapamycin

Intervention Description

Taken orally for at least 12 months

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Other Intervention Name(s)

Abbreviated MTX, Trade name:Trexall

Intervention Description

Given intravenously on the first, third and sixth day after transplant

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Other Intervention Name(s)

Prograf

Intervention Description

Taken orally or given intravenously for at least 6 months

Intervention Type

Drug

Intervention Name(s)

Cyclosporine

Other Intervention Name(s)

Brand names:, •Gengraf, •Neoral, •Sandimmune, •Sangcya

Intervention Description

Taken orally or given intravenously for at least 6 months

Intervention Type

Drug

Intervention Name(s)

MMF

Other Intervention Name(s)

Mycophenolate mofetil (MMF), Brand Names:, CellCept, Myfortic

Intervention Description

Taken orally for about 2 months

Primary Outcome Measure Information:

Title

Time Frame

2 years

Secondary Outcome Measure Information:

Title

To Compare 2-year Progression-free Survival Between the Two Treatment Arms

Time Frame

2 years

Title

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

Time Frame

2 years

Title

To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms

Time Frame

6 months

Title

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

Time Frame

2 years

Title

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.

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

72 Years

Accepts Healthy Volunteers

Eligibility Criteria

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Philippe Armand, MD, PhD

Organizational Affiliation

Dana-Farber Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Dana-Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55454

Country

United States

Facility Name

Ohio State University

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

26729448

Citation

Armand P, Kim HT, Sainvil MM, Lange PB, Giardino AA, Bachanova V, Devine SM, Waller EK, Jagirdar N, Herrera AF, Cutler C, Ho VT, Koreth J, Alyea EP, McAfee SL, Soiffer RJ, Chen YB, Antin JH. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol. 2016 Apr;173(1):96-104. doi: 10.1111/bjh.13931. Epub 2016 Jan 5.

Results Reference

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