Sirolimus, Tacrolimus, and Antithymocyte Globulin in Preventing Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant For Hematological Cancer
NCT ID: NCT00589563
Last Updated: 2014-09-10
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
32 participants
INTERVENTIONAL
2007-05-31
2012-02-29
Brief Summary
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PURPOSE: This phase II trial is studying how well sirolimus, tacrolimus, and antithymocyte globulin work in preventing graft-versus-host disease in patients undergoing a donor stem cell transplant for hematological cancer .
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Detailed Description
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Primary
* To determine the incidence and severity of acute- and chronic-graft-versus-host disease (GVHD) after HLA-matched or -mismatched unrelated donor hematopoietic peripheral blood transplantation in patients with hematologic malignancies scheduled to receive immunosuppressive combination of sirolimus, tacrolimus, and anti-thymocyte globulin as GVHD prophylaxis.
* To determine the safety of this combination in the first six months post-transplant.
Secondary
* To determine the time-to-engraftment, non-relapse mortality rate, overall and disease-free survival, incidence of disease relapse, and incidence of opportunistic infections with this GVHD prophylaxis.
OUTLINE: Patients are stratified according to conditioning regimen (fludarabine phosphate and melphalan vs fractionated total-body irradiation \[FTBI\] and etoposide vs FTBI and cyclophosphamide) and degree of donor/recipient HLA mismatch (high-risk vs low-risk).
* Conditioning regimen: Patients receive 1 of 3 standard conditioning regimens beginning on day -9 or -8 and continuing to day -1 or 0.
* Peripheral blood stem cell transplantation: Patients receive HLA-matched or mismatched unrelated donor peripheral blood stem cells on day 0.
* Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously beginning on day -3 and then orally when tolerated, oral sirolimus on days -3 and -2, anti-thymocyte globulin IV over 4-8 hours on days -3 to 0, and methotrexate\* IV on days 1, 3, and 6. Tacrolimus and sirolimus continue for 3-6 months (with taper).
NOTE: \*Only patients with high-risk HLA mismatch receive treatment with methotrexate.
After completion of study therapy, patients are followed periodically for up to 2 years.
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
SUPPORTIVE_CARE
NONE
Study Groups
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Fludarabine/Melphalan Conditioning
Fludarabine/Melphalan Conditioning with
Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
anti-thymocyte globulin
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
fludarabine phosphate
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant
melphalan
Melphalan 140 mg/m2 on day -4 from stem cell transplant
methotrexate
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant
sirolimus
Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.
Pediatric Patients \<40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose
tacrolimus
0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
allogeneic hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
peripheral blood stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
total-body irradiation
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
FTBI/Cytoxan Conditioning
FTBI/Cytoxan Conditioning with Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
anti-thymocyte globulin
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
cyclophosphamide
60mg/kg on days -5 and -4 from stem cell transplant
methotrexate
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant
sirolimus
Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.
Pediatric Patients \<40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose
tacrolimus
0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
allogeneic hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
peripheral blood stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
total-body irradiation
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
FTBI/Etoposide Conditioning
FTBI/Etoposide Conditioning with
Sirolimus, Tacrolimus and rabbit anti-thymocyte globulin (+/- methotrexate) for GvHD Prophylaxis
anti-thymocyte globulin
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
etoposide
60mg/kg on day -4 from stem cell transplant
methotrexate
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant
sirolimus
Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.
Pediatric Patients \<40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose
tacrolimus
0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
allogeneic hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
peripheral blood stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
total-body irradiation
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
Interventions
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anti-thymocyte globulin
0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.5 mg/kg on day -1 or day 0 from stem cell transplant
cyclophosphamide
60mg/kg on days -5 and -4 from stem cell transplant
etoposide
60mg/kg on day -4 from stem cell transplant
fludarabine phosphate
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant
melphalan
Melphalan 140 mg/m2 on day -4 from stem cell transplant
methotrexate
For high risk HLA-mismatch transplant only: 5 mg/m2 on days +1, +3 and +6 from stem cell transplant
sirolimus
Adults: 12 mg loading dose on day -3 from stem cell transplant followed by 4 mg orally single morning daily dose.
Pediatric Patients \<40kg: 3 mg/m2 orally on day -3 from stem cell transplant followed by 1 mg/m2 orally single morning daily dose
tacrolimus
0.02 mg/kd/d CIV beginning on day -3 from stem cell transplant
allogeneic hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
hematopoietic stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Fludarabine 25 mg/m2/d from days -9 to -5 from stem cell transplant, Melphalan 140 mg/m2 on day -4 from stem cell transplant
peripheral blood stem cell transplantation
The target peripheral blood stem cell dose will be 5-10 x 106/kg actual body weight
total-body irradiation
1320 cGy in 11 fractions from day -8 to day -5 or day -9 to day -6 prior to stem cell transplant
Eligibility Criteria
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Inclusion Criteria
* Diagnosis of hematological malignancy including any of the following:
* Non-Hodgkin lymphoma (NHL) in any complete remission (CR) or partial response (PR)
* Hodgkin lymphoma in any CR or PR
* Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in any CR
* Bone marrow blasts \< 20% within 4 weeks of transplant and peripheral blood absolute blast count \< 500/µL on the day of initiation of conditioning for patients with non-CR AML or ALL
* Myelodysplastic syndromes (MDS) treated or untreated
* Chronic myelogenous leukemia (CML) in chronic or accelerated phase
* Multiple myeloma in any CR or PR
* Chronic lymphocytic leukemia in CR or PR 2 or greater
* Myelofibrosis and other myeloproliferative disorders
* Bone marrow blasts \< 20% within 4 weeks of transplant and peripheral blood absolute blast count \< 500/µL on the day of initiation
* High-risk disease defined as AML or ALL \> CR1, accelerated phase CML, recurrent aggressive lymphoma, or active lymphoproliferative disease at transplant
* Low-risk disease defined as AML or ALL in CR1, chronic phase CML, or low-grade lymphoproliferative disorder with controlled disease at transplant
* Must be planning to receive 1 of the following conditioning regimens at City of Hope:
* Fludarabine phosphate and melphalan for patients with hematological malignancies and contraindications for conventional myeloablative regimens due to age, co-morbidity, or previous transplant
* Fractionated total-body irradiation (FTBI) and etoposide for patients with AML and ALL or CML in accelerated phase
* FTBI and cyclophosphamide for patients with NHL, AML, CML, and MDS
* Suitable unrelated donor available
* HLA-matched or mismatched
* Peripheral blood stem cells available
* No bone marrow or ex vivo-engineered or processed graft (e.g., CD34-positive, T-cell depletion)
* No uncontrolled CNS disease
PATIENT CHARACTERISTICS:
* Karnofsky performance status (PS) 70-100% or ECOG PS 0-2
* Creatinine \< 1.3 mg/dL or creatinine clearance ≥ 70 mL/min
* Ejection fraction \> 45%
* Direct bilirubin \< 3 times upper limit of normal (ULN)
* ALT and AST \< 3 times ULN
* Forced vital capacity, FEV1, and DLCO \> 45% of predicted
* Able to cooperate with oral medication intake
* No active donor or recipient serology positive for HIV
* No known contraindication to administration of sirolimus, tacrolimus, or anti-thymocyte globulin
* No active hepatitis B or C
* Negative pregnancy test
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Concurrent participation in other clinical trials for prevention or treatment of viral, bacterial, or fungal disease allowed provided agents do not interact with agents used in the current study
2 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
City of Hope Medical Center
OTHER
Responsible Party
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Principal Investigators
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Ryotaro Nakamura, MD
Role: STUDY_CHAIR
City of Hope Comprehensive Cancer Center
Locations
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Banner Good Samaritan Medical Center
Phoenix, Arizona, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Countries
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Other Identifiers
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CHNMC-06141
Identifier Type: -
Identifier Source: secondary_id
CDR0000579340
Identifier Type: REGISTRY
Identifier Source: secondary_id
06141
Identifier Type: -
Identifier Source: org_study_id
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