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

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

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.

Study Overview

• Status: Completed
• Conditions: Hodgkin Lymphoma; Non-hodgkin Lymphoma
• Intervention / Treatment: Drug: Sirolimus; Drug: Methotrexate; Drug: Tacrolimus; Drug: Cyclosporine; Drug: MMF

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 Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University Of Minnesota
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 72 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / 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: CellCept; Myfortic; Mycophenolate mofetil (MMF); Brand Names:

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
To Compare 2-year Progression-free Survival Between the Two Treatment Arms	2 years
To Compare the 2-year Cumulative Incidences of Disease Progression and of Non-relapse Mortality Between the Two Treatment Arms	2 years
To Compare the 180-day Cumulative Incidence of Grades II-IV and Grades III-IV Acute GVHD Between the Two Treatment Arms	6 months
To Compare the 2-year Cumulative Incidence of Chronic GVHD Between the Two Treatment Arms.	2 years
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

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI); Massachusetts General Hospital; Brigham and Women's Hospital
• Investigators: Principal Investigator: Philippe Armand, MD, PhD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: June 24, 2009
• First Submitted That Met QC Criteria: June 24, 2009
• First Posted (Estimate): June 25, 2009

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: January 30, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: GVHD; reduced intensity conditioning; graft versus host disease; allogeneic stem cell transplant; RIC transplantation
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Reproductive Control Agents; Antitubercular Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methotrexate; Tacrolimus; Mycophenolic Acid; Sirolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 09-073; CA142106 (Other Grant/Funding Number: National Cancer Institute/NIH/DHHS)