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| ID | Type | Description | Link |
|---|---|---|---|
| P30CA016086 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
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RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal cells. It also helps 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 or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease.
PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.
OBJECTIVES:
Primary
Secondary
OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type.
Preparative regimen:
Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover.
Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6.
Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD.
Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology.
After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methotrexate Only Arm | Active Comparator | GVHD Prophylaxis with Methotrexate |
|
| 2 Doses ATG + Methotrexate | Active Comparator | GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate |
|
| 2 Doses ATG | Active Comparator | GVHD prophylaxis with 2 doses ATG |
|
| 3 Doses ATG | Active Comparator |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| anti-thymocyte globulin | Biological | 0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Treatment-related Mortality | Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Complete Response at 6 and 12 Months Post-transplant | 6 and 12 months | |
| Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant | Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC). Chimerism was not tabulated on day 30. |
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DISEASE CHARACTERISTICS:
Histologically confirmed diagnosis of 1 of the following:
Chronic lymphocytic leukemia (CLL), meeting the following criteria:
Prolymphocytic leukemia (PLL), meeting the following criteria:
Chronic myelogenous leukemia (CML), meeting the following criteria:
Non-Hodgkin's lymphoma (NHL), meeting the following criteria:
Hodgkin's lymphoma, meeting the following criteria:
Multiple myeloma, meeting the following criteria:
Acute myeloid leukemia with documented control, defined as < 10% bone marrow blasts and no circulating blasts
Acute lymphoblastic leukemia, meeting the following criteria:
In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features:
Agnogenic myeloid metaplasia/myelofibrosis
Myelodysplastic syndromes (MDS) as defined by WHO criteria
Meets 1 of the following criteria:
Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible
HLA-matched or mismatched related donor or HLA-matched unrelated donor available
PATIENT CHARACTERISTICS:
PRIOR CONCURRENT THERAPY:
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| Name | Affiliation | Role |
|---|---|---|
| Thomas C. Shea, MD | UNC Lineberger Comprehensive Cancer Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill | Chapel Hill | North Carolina | 27599-7295 | United States |
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| Label | URL |
|---|---|
| University of North Carolina (UNC) Lineberger Comprehensive Cancer Center | View source |
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Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on protocol Lineberger Comprehensive Cancer Center (LCCC) 0306 at the University of North Carolina.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Trial Participants | All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg). |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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GVHD prophylaxis with 3 doses ATG
|
| sargramostim | Biological | GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20 |
|
| therapeutic allogeneic lymphocytes | Biological | A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0 |
|
| busulfan | Drug | 6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5 |
|
| fludarabine phosphate | Drug | fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3 |
|
| methotrexate | Drug | Methotrexate 5 mg/m^2 per day on days +1, +3 and +6 |
|
| tacrolimus | Drug | Suggested starting dose is 0.03 mg/kg po bid starting on Day -1 |
|
| nonmyeloablative allogeneic hematopoietic stem cell transplantation | Procedure | Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0 |
|
| peripheral blood stem cell transplantation | Procedure | Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0 |
|
| Days 30, 60, and 90 |
| 5-year Disease-free Survival | The length of time post-transplant that the patient survives without any signs or symptoms of that cancer. | Year 5 |
| Graft-vs-host Disease at 6 Months Post-transplant | Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:
Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled. Extensive chronic GVHD - Usually occurs at about three months post-transplant. | 6 Months |
| COMPLETED |
|
| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Trial Participants | All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Full Range | years |
| ||||||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| |||||||||||||||||||||||
| Region of Enrollment | Number | participants |
| |||||||||||||||||||||||
| Donor Types | Human leukocyte antigen (HLA) typing is used to match a recipient with a donor for bone marrow or cord blood transplant. Donor types are either HLA-matched related donor (MRD) or matched unrelated donor (MUD) or HLA-mismatched grafts. | Count of Participants | Participants |
| ||||||||||||||||||||||
| Comorbidity Index (CI) | The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed to identify relevant comorbidities in the allogeneic stem cell transplantation population and to enable risk assessment before allogeneic transplant. Comorbidities are given a a weighted score of 1 to 3 if present. The total score can range from 0 to 29, with higher numbers indicating more/worse comorbidities. The HCT-CI scores were further collapsed into 3 risk groups: 0 (low risk), 1 to 2 (intermediate risk), and 3 or more (high risk). | Median | Full Range | units on a scale |
| |||||||||||||||||||||
| Disease Risk Index (DRI) | The DRI uses a combination of a ternary breakdown for disease type and a binary breakdown for remission status to assign patients to 1 of 4 risk categories that differ very significantly (statistically and clinically) with respect to overall survival (OS) and Progression free survival (PFS). | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Treatment-related Mortality | Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse. | Posted | Number | percentage of participants | 6 months |
|
|
| |||||||||||||||||||||||||||
| Secondary | Complete Response at 6 and 12 Months Post-transplant | Complete response was not calculated at 6 and 12 months because the majority of patients had complete response at the time of transplant. | Posted | 6 and 12 months |
|
| ||||||||||||||||||||||||||||||
| Secondary | Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant | Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC). Chimerism was not tabulated on day 30. | Posted | Number | percentage of patients | Days 30, 60, and 90 |
|
| ||||||||||||||||||||||||||||
| Secondary | 5-year Disease-free Survival | The length of time post-transplant that the patient survives without any signs or symptoms of that cancer. | Posted | Number | percentage of participants | Year 5 |
|
| ||||||||||||||||||||||||||||
| Secondary | Graft-vs-host Disease at 6 Months Post-transplant | Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:
Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled. Extensive chronic GVHD - Usually occurs at about three months post-transplant. | Posted | Number | percentage of participants | 6 Months |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Trial Participants | All patients received IV fludarabine 30 mg/m2/day on days -7 through -3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days -6 through -5 and tacrolimus from day -1. Throughout the study duration, 8 different GVHD regimens were investigated. In addition to tacrolimus, patients received combinations of 3 agents: methotrexate (5 mg/m2 D1, 3, 6), rabbit antithymocyte globulin (ATG, 3 mg/kg to- 6 mg/kg) or alemtuzumab (Campath, 30 mg to- 90 mg). | 44 | 71 | 7 | 71 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hypoxemia | Blood and lymphatic system disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| graft failure | Blood and lymphatic system disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| liver toxicity/hyperbilirubinemia | Hepatobiliary disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| Graft vs host disease grade 4 | Gastrointestinal disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| CMV viremia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| subdural hematoma | Vascular disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| Fever | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| Failure to thrive | General disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| elevated lipase | Gastrointestinal disorders | CTCAE (2.0) | Non-systematic Assessment |
| |
| CMV pneumonia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| BK viruria | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| fungal pneumonia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| bronchiolitis obliterans organizing pneumonia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| EBV viremia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| nocardia pneumonia | Infections and infestations | CTCAE (2.0) | Non-systematic Assessment |
| |
| toxic epidermal nectrolysis | General disorders | CTCAE (2.0) | Non-systematic Assessment |
|
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Per the protocol, non-serious adverse events were not captured as this was a high-dose transplant study and grades 1,2, and 3 adverse events were expected. No unexpected toxicities were seen beyond those reported in the Serious Adverse Event section.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Thomas Shea | UNC Lineberger Comprehensive Cancer Center | 919-966-7746 | tom_shea@med.unc.edu |
| ID | Term |
|---|---|
| D009196 | Myeloproliferative Disorders |
| D007938 | Leukemia |
| D008223 | Lymphoma |
| D009101 | Multiple Myeloma |
| D054219 | Neoplasms, Plasma Cell |
| D009190 | Myelodysplastic Syndromes |
| D000013 | Congenital Abnormalities |
| D015463 | Leukemia, Prolymphocytic |
| D015465 | Leukemia, Myeloid, Accelerated Phase |
| D001752 | Blast Crisis |
| D015466 | Leukemia, Myeloid, Chronic-Phase |
| D018442 | Lymphoma, B-Cell, Marginal Zone |
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| D002051 | Burkitt Lymphoma |
| D006689 | Hodgkin Disease |
| D016403 | Lymphoma, Large B-Cell, Diffuse |
| D008228 | Lymphoma, Non-Hodgkin |
| D016400 | Lymphoma, Large-Cell, Immunoblastic |
| D015470 | Leukemia, Myeloid, Acute |
| D012008 | Recurrence |
| D054739 | Dendritic Cell Sarcoma, Interdigitating |
| D016410 | Lymphoma, T-Cell, Cutaneous |
| D008224 | Lymphoma, Follicular |
| D020522 | Lymphoma, Mantle-Cell |
| D009182 | Mycosis Fungoides |
| D012751 | Sezary Syndrome |
| D015451 | Leukemia, Lymphocytic, Chronic, B-Cell |
| D055728 | Primary Myelofibrosis |
| D008258 | Waldenstrom Macroglobulinemia |
| D054391 | Lymphoma, Extranodal NK-T-Cell |
| ID | Term |
|---|---|
| D001855 | Bone Marrow Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010265 | Paraproteinemias |
| D001796 | Blood Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007945 | Leukemia, Lymphoid |
| D015464 | Leukemia, Myelogenous, Chronic, BCR-ABL Positive |
| D007951 | Leukemia, Myeloid |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D002471 | Cell Transformation, Neoplastic |
| D063646 | Carcinogenesis |
| D009385 | Neoplastic Processes |
| D016393 | Lymphoma, B-Cell |
| D020031 | Epstein-Barr Virus Infections |
| D006566 | Herpesviridae Infections |
| D004266 | DNA Virus Infections |
| D014777 | Virus Diseases |
| D007239 | Infections |
| D014412 | Tumor Virus Infections |
| D015620 | Histiocytic Disorders, Malignant |
| D015614 | Histiocytosis |
| D016399 | Lymphoma, T-Cell |
| D015448 | Leukemia, B-Cell |
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| ID | Term |
|---|---|
| D000961 | Antilymphocyte Serum |
| C081222 | sargramostim |
| D002066 | Busulfan |
| C042382 | fludarabine phosphate |
| D008727 | Methotrexate |
| D016559 | Tacrolimus |
| D036102 | Peripheral Blood Stem Cell Transplantation |
| ID | Term |
|---|---|
| D007106 | Immune Sera |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D001688 | Biological Products |
| D045424 | Complex Mixtures |
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D018942 | Macrolides |
| D007783 | Lactones |
| D018380 | Hematopoietic Stem Cell Transplantation |
| D033581 | Stem Cell Transplantation |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D014180 | Transplantation |
| D013514 | Surgical Procedures, Operative |
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| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| High |
|
| Very High |
|
| Undetermined |
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|