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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms

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Trial Information

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


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.

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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care

Outcome Measure:

Incidence and severity of acute graft-versus-host disease (GVHD)

Outcome Time Frame:

Within 100 days after donor peripheral blood stem cell transplantation (PBSCT) as assessed by Glucksberg criteria

Safety Issue:

No

Principal Investigator

Zaid Al-Kadhimi, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Barbara Ann Karmanos Cancer Institute

Authority:

United States: Federal Government

Study ID:

CDR0000597130

NCT ID:

NCT00691015

Start Date:

May 2008

Completion Date:

January 2014

Related Keywords:

  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasms
  • 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
  • Neoplasms
  • Graft vs Host Disease
  • Leukemia
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Lymphoma, Large-Cell, Immunoblastic
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

Barbara Ann Karmanos Cancer InstituteDetroit, Michigan  48201