Clinical trial NCT00611351: Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer
Official title: Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation With a Conditioning Regimen of Targeted Busulfan, Cyclophosphamide, and Thymoglobulin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Graft Versus Host Disease
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Secondary Myelofibrosis
Keywords: graft versus host disease
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)
recurrent adult acute myeloid leukemia
untreated adult acute myeloid leukemia
untreated adult acute lymphoblastic leukemia
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
stage III multiple myeloma
refractory multiple myeloma
de novo myelodysplastic syndromes
myelodysplastic/myeloproliferative disease, unclassifiable
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
secondary myelofibrosis
secondary acute myeloid leukemia
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult T-cell leukemia/lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
recurrent adult acute lymphoblastic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
adult nasal type extranodal NK/T-cell lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
stage III adult T-cell leukemia/lymphoma
stage IV adult T-cell leukemia/lymphoma
stage III adult Burkitt lymphoma
stage IV adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage IV adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
atypical chronic myeloid leukemia
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
refractory hairy cell leukemia
stage I multiple myeloma
stage II multiple myeloma
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-02-08
Enrollment: 5
Sex: ALL
Minimum age (years): 19
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy before a donor bone marrow transplant or peripheral stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving busulfan together with cyclophosphamide and antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer.

Detailed description: OBJECTIVES:

Primary

* To determine the incidence of grade II-IV acute graft-versus-host disease in patients with hematologic cancer or other diseases treated with a myeloablative conditioning regimen comprising targeted (steady-state concentration of 800-1,000 ng/mL) busulfan, cyclophosphamide, and anti-thymocyte globulin followed by matched unrelated donor allogeneic hematopoietic stem cell transplantation.
* To determine the day +100 transplantation-related mortality in these patients.

Secondary

* To determine the effect of cyclophosphamide pharmacokinetic parameters on day +100 transplantation-related mortality in these patients.
* To determine the ability of low-dose anti-thymocyte globulin administered on day +5 to induce activation-induced cell death of activated donor lymphocytes.
* To determine the incidence of chronic graft-versus-host disease in patients treated with this regimen.
* To determine event-free and overall survival of patients treated with this regimen.
* To evaluate pharmacogenomic associations between genetic polymorphisms in drug disposition enzymes with the pharmacokinetics of busulfan and cyclophosphamide.

OUTLINE:

* Myeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -8 to -5; cyclophosphamide IV over 4 hours on days -3 to -2; and anti-thymocyte globulin IV over 6 hours on day -3 and then over 4 hours on days -2, -1, and 5.
* Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell infusion on day 0.
* Graft-versus-host-disease prophylaxis: Patients receive tacrolimus IV continuously or orally on days 6 to150, followed by an even taper to day 180 in the absence of graft-versus-host-disease. Patients also receive mycophenolate mofetil IV or orally beginning on day 6 and continuing to day 28.

Patients undergo blood collection periodically during study for pharmacokinetic, pharmacogenomic, and other translational studies. Genomic DNA extracted from blood samples is analyzed by polymerase chain reaction for genetic polymorphisms in cyclophosphamide/busulfan disposition enzymes. Activated donor lymphocytes are assessed using flow cytometry to measure activation-induced cell death, as reflected by apoptosis in activated T cells. Chimerism on or around day 100 is also assessed using fluorescence in situ hybridization analysis and DNA fingerprinting.

After completion of study treatment, patients are followed periodically.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed diagnosis of 1 of the following:

  * Acute myeloid leukemia
  * Acute lymphocytic leukemia
  * Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis)
  * Multiple myeloma
  * Myelodysplastic syndromes
  * Malignant lymphoma
  * Myelofibrosis
* Requirement for myeloablative conditioning regimen confirmed by attending physician
* Available donor must meet the following criteria:

  * HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens
  * Matched at the A, B, and DRβ1 loci
  * Single HLA-A or HLA-B antigen mismatch allowed
  * Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors
  * Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed
* Karnofsky performance status 70-100%
* DLCO ≥ 50% predicted
* LVEF ≥ 45%
* Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min
* Serum total bilirubin ≤ 2.0 mg/dL
* Fertile patients must use effective contraception

Exclusion Criteria:

* No active uncontrolled infection
* Not pregnant or nursing/negative pregnancy test
* No HIV infection
* No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy

Primary outcomes:
measure: Transplantation-related Mortality at 100 Days Post-transplantation
timeFrame: at the 100 days post-transplant
Secondary outcomes:
measure: Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
timeFrame: at day 100 post transplantation
measure: Overall Survival
timeFrame: 2 years post transplant
measure: Event-free Survival
timeFrame: 2 years post transplant
Other outcomes:
Locations:
city: Omaha
country: United States
facility: Unversity of Nebraska Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Marcel Devetten, MD
role: PRINCIPAL_INVESTIGATOR
References: