Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant

May 26, 2017 updated by: Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute

A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin®, as Graft-versus-Host- Disease Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

RATIONALE: Giving low doses of chemotherapy, monoclonal antibodies, and radiation therapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, and antithymocyte globulin before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying the side effects of giving sirolimus together with tacrolimus and antithymocyte globulin and to see how well it works in preventing graft-versus-host disease in patients with hematologic cancer who are undergoing donor stem cell transplant.

Study Overview

Detailed Description

OBJECTIVES:

Primary

  • To determine the incidence and severity of acute graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor peripheral blood stem cell transplantation (PBSCT) in patients with hematologic malignancies treated with immunosuppressive therapy comprising sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
  • To determine the safety of this regimen in these patients at 6 months after PBSCT.

Secondary

  • To determine the time to engraftment (i.e., platelet and absolute neutrophil recovery) in patients treated with this regimen.
  • To determine the length of hospital stay of these patients within 100 days after PBSCT.
  • To determine the incidence of infections, including CMV and EBV reactivation and post-transplant lymphoproliferative disorders, in patients treated with this regimen.
  • To determine the incidence of thrombotic microangiopathy and veno-occlusive disease in patients treated with this regimen.
  • To determine the incidence of chronic GVHD in patients treated with this regimen.
  • To determine the overall and disease-free survival of these patients at 2 years after PBSCT.
  • To determine the Karnofsky performance status of these patients at baseline and at various time points after PBSCT.
  • To conduct immunocorrelative studies prior to and at various time points after PBSCT.

OUTLINE:

  • Conditioning regimen: Patients receive 1 of 6 conditioning regimens (standard of care treatment) between days -9 and -3, based on diagnosis and the treating physician's preference regarding regimen intensity.

    • Regimen I: Patients receive fludarabine phosphate IV and busulfan IV.
    • Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
    • Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
    • Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
    • Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
    • Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI.
  • Allogeneic peripheral blood stem cell transplantation: Patients undergo filgrastim (G-CSF)-mobilized allogeneic peripheral blood stem cell transplantation on day 0.
  • Graft-versus-host disease prophylaxis (GVHD): Patients receive tacrolimus IV continuously over 24 hours or orally and sirolimus orally beginning on day -3 and continuing until day 30 or day 90, followed by a taper in the absence of GVHD. Patients also receive anti-thymocyte globulin IV over 4-8 hours on days -3 to -1.

Blood samples are obtained at baseline and periodically during study for correlative biomarker studies. Samples are analyzed by T-cell immunophenotyping, absolute subset number quantification, and multi-parameter flow cytometry for evaluation of immune reconstitution, T-cell differentiation status, NK-cell recovery, allo-reactivity of donor T-cells after transplantation, and regulatory T-cell reconstitution.

After completion of study therapy, patients are followed periodically for up to 2 years.

Study Type

Interventional

Enrollment (Actual)

48

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Michigan
      • Detroit, Michigan, United States, 48201-1379
        • Barbara Ann Karmanos Cancer Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Diagnosis of a hematological malignancy, including any of the following:

    • Non-Hodgkin lymphoma in complete remission (CR) or partial remission (PR)
    • Hodgkin lymphoma in CR or PR
    • Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) meeting either of the following criteria:

      • In CR
      • Not in CR and meets the following criteria:

        • Bone marrow blast < 20% within 4 weeks of transplantation
        • Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
    • Myelodysplastic syndromes, treated or untreated
    • Chronic myeloid leukemia in chronic phase or accelerated phase
    • Multiple myeloma in CR or PR
    • Chronic lymphocytic leukemia in second or greater CR or PR
    • Myelofibrosis or other myeloproliferative disorders meeting the following criteria:

      • Bone marrow blasts < 20% within 4 weeks of transplantation
      • Peripheral blood absolute blast count < 500 per microliter on the day of initiating conditioning therapy
      • Patients with ascites not allowed
  • No prior bone marrow or ex vivo engineered or processed graft (i.e., CD34+ enrichment, T-cell depletion, etc)
  • Scheduled to undergo peripheral blood stem cell transplantation from a suitable HLA-matched or -mismatched unrelated donor, as determined by treating physician

    • High resolution molecular HLA typing is required for HLA class I and II
    • No more than one antigen or allele mismatch
  • No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-2
  • Karnofsky PS 60-100%
  • Creatinine clearance > 50 mL/min
  • Bilirubin < 3 times upper limit of normal (ULN)
  • ALT and AST < 3 times ULN
  • LVEF > 50%
  • FVC, FEV_1, or DLCO > 50% predicted

    • Patients on home oxygen not allowed
  • Able to cooperate with oral medication intake
  • HIV negative
  • No active hepatitis B or hepatitis C
  • No known contraindication to sirolimus, tacrolimus, or anti-thymocyte globulin

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Chemotherapy or chemotherapy + total body irradiation

Standard of care (SOC) chemotherapy or ( SOC) chemotherapy + total body irradiation (TBI) of one of the following regimens:

Regimen I: Patients receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV.

Regimen II: Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV;anti-thymocyte globulin IV.

Regimen III: Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV; anti-thymocyte globulin IV.

Regimen IV: Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV; anti-thymocyte globulin IV.

Regimen V: Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV; anti-thymocyte globulin IV.

Regimen VI: Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI; anti-thymocyte globulin IV.

Given IV
Other Names:
  • Fludara®
Given IV
Other Names:
  • Cytoxan
  • Neosar
  • Cytoxan Lyophilized
Given IV
Other Names:
  • Rituxan
  • MabThera
  • Zytux
Given IV
Other Names:
  • Bicnu
  • Gliadel
Given IV
Other Names:
  • Toposar
  • Etopophos
Given IV
Other Names:
  • Depocyt
Given IV
Other Names:
  • Alkeran
Given IV
Other Names:
  • Busulfex
  • Myleran
Given once or twice daily
Other Names:
  • radiotherapy
Given IV
Other Names:
  • Thymoglobulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Incidence of Acute Graft-versus-host Disease (GVHD)
Time Frame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
Severity of Acute Graft-versus-host Disease (GVHD)
Time Frame: Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria
Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment.
Time Frame: Within 6 months after PBSCT
Within 6 months after PBSCT

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of Chronic GVHD.
Time Frame: Within 2 years after PBSCT
Within 2 years after PBSCT
Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] )
Time Frame: post transplant, up to 4 weeks
post transplant, up to 4 weeks
Overall Survival.
Time Frame: At 2 years after PBSCT
At 2 years after PBSCT
Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders)
Time Frame: Within 6 months after PBSCT
Within 6 months after PBSCT
Karnofsky Performance Status Performance Status
Time Frame: At 90 days after PBSCT

100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs.

50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital admission is indicated although death not imminent.

20 - Very sick; hospital admission necessary; active supportive treatment necessary.

10 - Moribund; fatal processes progressing rapidly. 0 - Dead

At 90 days after PBSCT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Zaid Al-Kadhimi, MD, Barbara Ann Karmanos Cancer Institute

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2008

Primary Completion (Actual)

April 1, 2014

Study Completion (Actual)

April 1, 2014

Study Registration Dates

First Submitted

June 4, 2008

First Submitted That Met QC Criteria

June 4, 2008

First Posted (Estimate)

June 5, 2008

Study Record Updates

Last Update Posted (Actual)

June 28, 2017

Last Update Submitted That Met QC Criteria

May 26, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 2007-127 (Other Identifier: Barbara Ann Karmanos Cancer Institute)
  • P30CA022453 (U.S. NIH Grant/Contract)
  • GENZ-WSU-2007-127

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Lymphoma

Clinical Trials on fludarabine phosphate

3
Subscribe