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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2012 by Barbara Ann Karmanos Cancer Institute.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Information provided by:
Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier:
NCT00691015
First received: June 4, 2008
Last updated: August 6, 2012
Last verified: August 2012
  Purpose

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.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Biological: rituximab
Drug: busulfan
Drug: carmustine
Drug: cyclophosphamide
Drug: cytarabine
Drug: etoposide
Drug: fludarabine phosphate
Drug: melphalan
Radiation: total-body irradiation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Supportive Care
Official Title: A Phase II Study of Sirolimus, Tacrolimus and Thymoglobulin®, as Graft-versus-Host- Disease Prophylaxis in Patients Undergoing Unrelated Donor Hematopoietic Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Barbara Ann Karmanos Cancer Institute:

Primary Outcome Measures:
  • Incidence and 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 ] [ Designated as safety issue: No ]
  • Safety, as defined by serious adverse events and adverse events related to study treatment. [ Time Frame: Within 6 months after PBSCT ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence of chronic GVHD. [ Time Frame: Within 2 years after PBSCT ] [ Designated as safety issue: No ]
  • Time to engraftment (i.e., absolute neutrophil recovery [ANC > 1,500/mm³] and platelet recovery [platelet count > 25,000/mm³]) [ Time Frame: At screening, post transplant, 30, 60, 90 & 180 days after PBSCT ] [ Designated as safety issue: No ]
  • Overall and disease-free survival. [ Time Frame: At 2 years after PBSCT ] [ Designated as safety issue: No ]
  • Length of hospital stay. [ Time Frame: Within 100 days after PBSCT ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Incidence of thrombotic microangiopathy [ Time Frame: Within 100 days after PBSCT ] [ Designated as safety issue: No ]
  • Karnofsky performance status [ Time Frame: At baseline and at 100 days, 6 months, 1 year, and 2 years after PBSCT ] [ Designated as safety issue: No ]
  • Biomarkers and immunocorrelative studies (i.e., T-cell, B-cell, NK-cell, regulatory T-cell, and allo-reactive T-cell quantitation studies by flow cytometry) [ Time Frame: At 30, 60, 90, and 180 days after PBSCT ] [ Designated as safety issue: No ]

Enrollment: 48
Study Start Date: May 2008
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Conditioning regimen I
Patients receive fludarabine phosphate IV and busulfan IV.
Drug: busulfan
Given IV
Drug: fludarabine phosphate
Given IV
Experimental: Conditioning regimen II
Patients undergo total body irradiation (TBI) twice daily for 8 fractions and receive etoposide IV.
Drug: etoposide
Given IV
Radiation: total-body irradiation
Given once or twice daily
Experimental: Conditioning regimen III
Patients undergo TBI once or twice daily for 11 fractions and receive cyclophosphamide IV.
Drug: cyclophosphamide
Given IV
Radiation: total-body irradiation
Given once or twice daily
Experimental: Conditioning regimen IV
Patients undergo TBI and receive fludarabine phosphate IV and busulfan IV.
Drug: busulfan
Given IV
Drug: fludarabine phosphate
Given IV
Experimental: Conditioning regimen V
Patients receive carmustine IV, etoposide IV, cytarabine IV, and melphalan IV. Some patients also receive rituximab IV.
Biological: rituximab
Given IV
Drug: carmustine
Given IV
Drug: cytarabine
Given IV
Drug: etoposide
Given IV
Drug: melphalan
Given IV
Experimental: Conditioning regimen VI
Patients receive fludarabine phosphate IV and melphalan IV. Some patients also undergo TBI.
Drug: fludarabine phosphate
Given IV
Drug: melphalan
Given IV
Radiation: total-body irradiation
Given once or twice daily

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00691015

Locations
United States, Michigan
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States, 48201-1379
Sponsors and Collaborators
Barbara Ann Karmanos Cancer Institute
Investigators
Study Chair: Zaid Al-Kadhimi, MD Barbara Ann Karmanos Cancer Institute
  More Information

Additional Information:
No publications provided

Responsible Party: Zaid Al-Kadhimi, Barbara Ann Karmanos Cancer Institute
ClinicalTrials.gov Identifier: NCT00691015     History of Changes
Other Study ID Numbers: CDR0000597130, P30CA022453, WSU-2007-127, GENZ-WSU-2007-127
Study First Received: June 4, 2008
Last Updated: August 6, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Barbara Ann Karmanos Cancer Institute:
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult Hodgkin lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
noncontiguous stage II adult Burkitt lymphoma

Additional relevant MeSH terms:
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Graft vs Host Disease
Plasmacytoma
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Lymphoma
Leukemia
Syndrome
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Precancerous Conditions
Lymphatic Diseases
Disease
Pathologic Processes
Cyclophosphamide
Cytarabine

ClinicalTrials.gov processed this record on September 22, 2014