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

Primary Purpose

Chronic Myeloproliferative Disorders, Leukemia, Lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
rituximab
busulfan
carmustine
cyclophosphamide
cytarabine
etoposide
fludarabine phosphate
melphalan
total body irradiation (TBI)
anti-thymocyte globulin IV
Sponsored by
Barbara Ann Karmanos Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Chronic Myeloproliferative Disorders focused on measuring 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, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), chronic phase chronic myelogenous leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, primary myelofibrosis, atypical chronic myeloid leukemia, BCR-ABL negative, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia

Eligibility Criteria

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

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

Sites / Locations

  • Barbara Ann Karmanos Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Chemotherapy or chemotherapy + total body irradiation

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of Acute Graft-versus-host Disease (GVHD)
Severity of Acute Graft-versus-host Disease (GVHD)
Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment.

Secondary Outcome Measures

Incidence of Chronic GVHD.
Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] )
Overall Survival.
Incidence of Infections, Including Bacterial, Fungal, and Viral Infections (i.e., CMV and EBV Reactivation, Including Post-transplant Lymphoproliferative Disorders)
Karnofsky Performance Status Performance Status
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

Full Information

First Posted
June 4, 2008
Last Updated
May 26, 2017
Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00691015
Brief Title
Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer Who Are Undergoing Donor Stem Cell Transplant
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
May 2008 (undefined)
Primary Completion Date
April 2014 (Actual)
Study Completion Date
April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Barbara Ann Karmanos Cancer Institute
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms
Keywords
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, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), chronic phase chronic myelogenous leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasm, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, primary myelofibrosis, atypical chronic myeloid leukemia, BCR-ABL negative, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, chronic neutrophilic leukemia

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chemotherapy or chemotherapy + total body irradiation
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
Rituxan, MabThera, Zytux
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
Busulfex, Myleran
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
carmustine
Other Intervention Name(s)
Bicnu, Gliadel
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Cytoxan, Cytoxan Lyophilized, Neosar
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
Depocyt
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
Etopophos, Toposar
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
Fludara®
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
melphalan
Other Intervention Name(s)
Alkeran
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
total body irradiation (TBI)
Other Intervention Name(s)
radiotherapy
Intervention Description
Given once or twice daily
Intervention Type
Drug
Intervention Name(s)
anti-thymocyte globulin IV
Other Intervention Name(s)
Thymoglobulin
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
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
Title
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
Title
Safety, as Defined by Serious Adverse Events and Adverse Events Related to Study Treatment.
Time Frame
Within 6 months after PBSCT
Secondary Outcome Measure Information:
Title
Incidence of Chronic GVHD.
Time Frame
Within 2 years after PBSCT
Title
Time to Engraftment (i.e., Absolute Neutrophil Recovery [ANC > 500/mm³] )
Time Frame
post transplant, up to 4 weeks
Title
Overall Survival.
Time Frame
At 2 years after PBSCT
Title
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
Title
Karnofsky Performance Status Performance Status
Description
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
Time Frame
At 90 days after PBSCT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zaid Al-Kadhimi, MD
Organizational Affiliation
Barbara Ann Karmanos Cancer Institute
Official's Role
Study Chair
Facility Information:
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201-1379
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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