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

NCT ID: NCT00691015

Last Updated: 2017-06-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-05-31
• Study Completion Date: 2014-04-30

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.

Conditions

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

rituximab

Intervention Type: BIOLOGICAL

Given IV

busulfan

Intervention Type: DRUG

Given IV

carmustine

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

cytarabine

Intervention Type: DRUG

Given IV

etoposide

Intervention Type: DRUG

Given IV

fludarabine phosphate

Intervention Type: DRUG

Given IV

melphalan

Intervention Type: DRUG

Given IV

total body irradiation (TBI)

Intervention Type: RADIATION

Given once or twice daily

anti-thymocyte globulin IV

Intervention Type: DRUG

Given IV

Interventions

rituximab

Given IV

Intervention Type: BIOLOGICAL

busulfan

Given IV

Intervention Type: DRUG

carmustine

Given IV

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

cytarabine

Given IV

Intervention Type: DRUG

etoposide

Given IV

Intervention Type: DRUG

fludarabine phosphate

Given IV

Intervention Type: DRUG

melphalan

Given IV

Intervention Type: DRUG

total body irradiation (TBI)

Given once or twice daily

Intervention Type: RADIATION

anti-thymocyte globulin IV

Given IV

Intervention Type: DRUG

Other Intervention Names

Rituxan; MabThera; Zytux; Busulfex; Myleran; Bicnu; Gliadel; Cytoxan; Cytoxan Lyophilized; Neosar; Depocyt; Etopophos; Toposar; Fludara®; Alkeran; radiotherapy; Thymoglobulin

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Barbara Ann Karmanos Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Zaid Al-Kadhimi

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Zaid Al-Kadhimi, MD

Role: STUDY_CHAIR

Barbara Ann Karmanos Cancer Institute

Locations

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States

Countries

United States

Other Identifiers

P30CA022453

Identifier Type: NIH

Identifier Source: secondary_id

View Link

GENZ-WSU-2007-127

Identifier Type: -

Identifier Source: secondary_id

2007-127

Identifier Type: OTHER

Identifier Source: secondary_id

2007-127

Identifier Type: -

Identifier Source: org_study_id