Busulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
NCT ID: NCT00245037
Last Updated: 2017-09-27
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
147 participants
INTERVENTIONAL
2005-06-30
2015-08-31
Brief Summary
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PURPOSE: This phase I/II trial is studying the side effects of giving busulfan and fludarabine together with total-body irradiation and to see how well they work in treating patients who are undergoing a donor stem cell transplant for hematologic cancer.
Detailed Description
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Primary
* To assess safety and toxicity of the addition of busulfan added to an established fludarabine and low-dose total-body irradiation (TBI) conditioning regimen for non-myeloablative allogeneic transplantation in patients with hematologic malignancies. (Phase I)
* To assess the non-relapse mortality 1-year after conditioning with busulfan and fludarabine/TBI in patients with hematologic malignancies at moderate to high risk for graft rejection and/or relapse of underlying disease. (Phase II)
Secondary
* To assess overall survival 1-year survival. (Phase II)
* To assess the incidence of graft rejection. (Phase II)
* To assess the incidence of grade II-IV acute graft-vs-host disease (GVHD) and chronic extensive GVHD. (Phase II)
* To assess rates of disease progression and/or relapse-related mortality. (Phase II)
* To determine non-hematologic grade III-IV organ specific toxicity. (Phase II)
OUTLINE:
* Nonmyeloablative-conditioning regimen: Patients receive busulfan IV on day -5 and fludarabine IV over 30 minutes on days -4 to -2. Patients undergo total body irradiation on day 0.
* Allogeneic peripheral blood stem cell transplantation (PBSC): Patients undergo donor PBSC infusion on day 0.
* Graft-versus-host disease prophylaxis: Patients receive oral cyclosporine twice daily on days -3 to 56 followed by a taper to day 180. Patients with a related stem cell donor receive oral mycophenolate mofetil twice daily on days 0-28. Patients with an unrelated stem cell donor receive oral mycophenolate mofetil 3 times daily on days 0-28 followed by a taper twice daily to day 56. Patients with evidence of relapse or persistent disease may also receive up to 3 donor lymphocyte infusions.
PROJECTED ACCRUAL: A total of 225 patients will be accrued for this study; 25 patients accrued into the Phase I and 200 patients into Phase II.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Busulfan (Bu), Fludarabine (Flu), Total Body Iradiation (TBI)
Busulfan 3.2 mg/kg IV on day -5 Fludarabine 30 mg/m2/day x 3 (total dose 90 mg/m2, day -4 to day -2 TBI 200 centigray (cGy) x 1, day 0
therapeutic allogeneic lymphocytes
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.
busulfan
Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative.
IV busulfan is available and diluted and administered per package insert guidelines.
cyclosporine
Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including Interleukin 2 (IL-2) and Interleukin 4 (IL-4).
\- Starting on day -3, Cyclosporine (CSP) is given at a dose of 4.0 mg/kg p.o. b.i.d.
fludarabine phosphate
Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and ribonucleotide nuclease.
* Dosing: Days -4, -3 and -2: Fludarabine 30 mg/m2/day IV. Total dose equals 90 mg/m2.
* Monitoring: Fludarabine level is not monitored.
* Dose Adjustments: There are no provisions for fludarabine dose adjustments.
mycophenolate mofetil
Mycophenolate mofetil (MMF) is the morpholinyl ethyl ester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B- and T-lymphocytes is blocked and antibody production is inhibited.
* Related Donors: MMF will be given daily at 15mg/kg q 12 hrs until day +28, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
* Unrelated Donors: MMF will be given daily at 15mg/kg q 8 hrs until day +28, then given daily at 15mg/kg q 12 hours until day +56, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
peripheral blood stem cell transplantation
Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:
* In autologous transplants, patients receive their own stem cells.
* In syngeneic transplants, patients receive stem cells from their identical twin.
* In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Total Body Irradiation (TBI)
TBI is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of radiation-induced lung injury.
* Toxicities: At the dosage used, side effects are not expected. Nevertheless, there may be fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including cataract formation, pulmonary damage, carcinogenesis, and sterilization.
* Dosing: TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 15-19 cGy/min.
Granulocyte colony-stimulating factor (G-CSF)
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.
* Toxicities: At the dosage used, the most common side effect will be medullary bone pain.
* Dosing: 5 mcg/kg/day given per institutional standards (on approximately days 10-15 or not at all).
Phenytoin
This drug is used to prevent seizures while on chemotherapy.
Methotrexate
Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.
Interventions
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therapeutic allogeneic lymphocytes
A population of lymphocytes therapeutically administered to a recipient individual who is genetically distinct from a donor of the same species.
busulfan
Busulfan is an alkylating chemotherapeutic agent which has been used in many high dose and reduced intensity regimens prior to allogeneic or autologous hematopoietic stem cell transplants. It is active in a wide variety of malignancies and in high-doses it is myeloablative.
IV busulfan is available and diluted and administered per package insert guidelines.
cyclosporine
Cyclosporine is a cyclic polypeptide immunosuppressive agent. It blocks the calcium-dependent calcineurin-mediated nuclear localization of nuclear factor of activated T cells (NFAT) following T-cell activation, thereby inhibiting transactivation of key T-cell response genes including Interleukin 2 (IL-2) and Interleukin 4 (IL-4).
\- Starting on day -3, Cyclosporine (CSP) is given at a dose of 4.0 mg/kg p.o. b.i.d.
fludarabine phosphate
Fludarabine's active metabolite 2-fluoro-ara-A is an antimetabolite that inhibits DNA primase, DNA polymerase alpha and ribonucleotide nuclease.
* Dosing: Days -4, -3 and -2: Fludarabine 30 mg/m2/day IV. Total dose equals 90 mg/m2.
* Monitoring: Fludarabine level is not monitored.
* Dose Adjustments: There are no provisions for fludarabine dose adjustments.
mycophenolate mofetil
Mycophenolate mofetil (MMF) is the morpholinyl ethyl ester of mycophenolic acid (MPA) and reversibly inhibits inosine monophosphate dehydrogenase, particularly the type II isoform that is more prominent in activated lymphocytes. As a result of the inhibition of de novo purine synthesis, proliferation of B- and T-lymphocytes is blocked and antibody production is inhibited.
* Related Donors: MMF will be given daily at 15mg/kg q 12 hrs until day +28, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
* Unrelated Donors: MMF will be given daily at 15mg/kg q 8 hrs until day +28, then given daily at 15mg/kg q 12 hours until day +56, then stop without tapering. Doses will be rounded to the nearest 250 mg (capsules are 250 mg).
peripheral blood stem cell transplantation
Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:
* In autologous transplants, patients receive their own stem cells.
* In syngeneic transplants, patients receive stem cells from their identical twin.
* In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Total Body Irradiation (TBI)
TBI is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in modern practice the lungs are often partially shielded to lower the risk of radiation-induced lung injury.
* Toxicities: At the dosage used, side effects are not expected. Nevertheless, there may be fever, alopecia, parotitis, diarrhea, reversible skin pigmentation, mucositis and late effects including cataract formation, pulmonary damage, carcinogenesis, and sterilization.
* Dosing: TBI will be given in one 200 cGy fraction from linear accelerator at a rate of 15-19 cGy/min.
Granulocyte colony-stimulating factor (G-CSF)
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.
* Toxicities: At the dosage used, the most common side effect will be medullary bone pain.
* Dosing: 5 mcg/kg/day given per institutional standards (on approximately days 10-15 or not at all).
Phenytoin
This drug is used to prevent seizures while on chemotherapy.
Methotrexate
Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on some areas of the body) that cannot be controlled by other treatments.
Eligibility Criteria
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Inclusion Criteria
* Diagnosis of a hematologic malignancy of 1 of the following high-risk types:
* Acute lymphoblastic leukemia
* Acute myeloid leukemia
* Chronic myelogenous leukemia
* Chronic lymphocytic leukemia
* Myelodysplastic syndromes
* Myeloproliferative disorder
* Multiple myeloma
* Plasma cell dyscrasias
* Non-Hodgkin lymphoma
* Hodgkin disease
PATIENT CHARACTERISTICS:
Performance status
* Karnofsky 50-100%
Life expectancy
* Not specified
Hematopoietic
* Not specified
Hepatic
* No liver failure
* No cirrhosis with evidence of portal hypertension
* No alcoholic hepatitis
* No esophageal varices
* No chronic hepatitis
* No other liver disease
Renal
* Not specified
Cardiovascular
* Left Ventricular Ejection Fraction (LVEF) \> 35%
* No symptomatic coronary artery disease or cardiac failure requiring therapy
Pulmonary
* Diffusing capacity of lung for carbon monoxide (DLCO) \> 30%
* Total lung capacity \> 30%
* Forced expiratory volume in 1 second (FEV\_1) \> 30%
* No supplementary continuous oxygen
Other
* HIV negative
* No active nonhematologic malignancy except localized skin cancer
* No overt organ dysfunction
PRIOR CONCURRENT THERAPY:
* Not specified
18 Years
80 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
OHSU Knight Cancer Institute
OTHER
Responsible Party
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Richard Maziarz
Principal Investigator
Principal Investigators
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Richard Maziarz, MD
Role: STUDY_CHAIR
OHSU Knight Cancer Institute
Locations
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Knight Cancer Institute at Oregon Health and Science University
Portland, Oregon, United States
Countries
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Other Identifiers
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OHSU-HEM-05011-L
Identifier Type: OTHER
Identifier Source: secondary_id
OHSU-210
Identifier Type: OTHER
Identifier Source: secondary_id
IRB00000210
Identifier Type: -
Identifier Source: org_study_id