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| ID | Type | Description | Link |
|---|---|---|---|
| UCSF-04152 | Other Identifier | UCSF Helen Diller Family Comprehensive Cancer Center | |
| UCSF-00452 | Other Identifier | UCSF Helen Diller Family Comprehensive Cancer Center | |
| UCSF-H411-25738-02 | Other Identifier | UCSF Committee on Human Research (CHR) |
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
RATIONALE: Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine and busulfan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell, bone marrow , or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine together with methotrexate and methylprednisolone may stop this from happening.
PURPOSE: This phase II trial is studying how well giving alemtuzumab together with fludarabine and busulfan works when given before donor stem cell transplant in treating young patients with hematologic disorders.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study.
Conditioning regimen: Patients receive alemtuzumab IV over 6 hours on days -12 to -10, high-dose busulfan IV over 2 hours 4 times daily on days -9 to -6, and fludarabine IV over 30 minutes on days -5 to -2.
Allogeneic stem cell transplantation: Two days after the completion of conditioning regimen, patients undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
Graft-vs-host disease (GVHD) prophylaxis:
After transplantation, patients are followed periodically for up to 20 years.
PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Single arm - conditioning and transplant | Experimental | Alemtuzumab 0.5 mg/kg (maximum 15 mg) daily for 3 days; Busulfan i.v. every 6 hours from day -9 to day -6 for 16 total doses; Fludarabine phosphate from day -5 for 4 days at 1.3 mg/kg (if patient was less than 12 kg) or 40 mg/m*2 per dose; Cyclosporine continuous infusion 3 mg/kg/Day beginning day -1 for GVHD prophylaxis; Methotrexate at 15 mg/m*2 on day +1, 10 mg/m*2 on days +3, +6, and (only for MUDs) day +11 also for GVHD prophylaxis; Methylprednisolone only as required for GVHD prophylaxis; allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation or peripheral blood stem cell transplantation or umbilical cord blood transplantation. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| alemtuzumab | Biological |
| ||
| busulfan |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation | Peripheral blood chimerism studies were performed by quantitative real time polymerase chain reaction (qPCR) evaluation of differential short tandem repeat DNA sequences | 6 weeks post-transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment-related Mortality at 100 Days and 1 Year Post Transplantation | 100 days and 1 year | |
| Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation | 1 year post-transplantation |
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DISEASE CHARACTERISTICS:
Diagnosis of 1 of the following hematologic conditions:
Aplastic anemia with marrow aplasia, meeting all of the following criteria:
Chronic aplastic anemia, meeting all of the following criteria:
Congenital marrow failure syndrome, including any of the following (with closely matched related or unrelated donor):
Hemoglobinopathy (with closely matched related or unrelated donor)
Severe immunodeficiency disease
Other stem cell defects (e.g., osteopetrosis)
Severe immune dysregulation/autoimmune disorders
Chronic myelogenous leukemia
Acute myeloid leukemia
Myelodysplastic syndromes
Inborn errors of metabolism
Histiocytosis
No severe combined immunodeficiency disease
Matched related or unrelated donor available by high resolution DNA typing
Related donor, meeting both of the following criteria:
Unrelated donor, meeting 1 of the following criteria:
PATIENT CHARACTERISTICS:
PRIOR CONCURRENT THERAPY:
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| Name | Affiliation | Role |
|---|---|---|
| Morton J. Cowan, MD | University of California, San Francisco | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCSF Helen Diller Family Comprehensive Cancer Center | San Francisco | California | 94115 | United States | ||
Patients were ineligible if a cord blood was being used for the transplant or if they met any of the other ineligibility criteria in the protocol or did not meet eligibility criteria such as having Fanconi's Anemia.
Subjects recruited from 9/2005 through 9/2010. Patients identified by the Pediatric BMT (Bone Marrow Transplant) Program and consented by study investigators as outpatients in the BMT clinic.
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| ID | Title | Description |
|---|---|---|
| FG000 | Single Arm - Transplant Pre-conditioning Per Study Protocol | All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Drug |
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| cyclosporine | Drug |
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| fludarabine phosphate | Drug |
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| methotrexate | Drug |
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| methylprednisolone | Drug |
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| allogeneic bone marrow transplantation | Procedure |
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| allogeneic hematopoietic stem cell transplantation | Procedure |
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| peripheral blood stem cell transplantation | Procedure |
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| umbilical cord blood transplantation | Procedure |
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| Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | polymerase chain reaction testing for presence of CMV weekly until at least day +100 then every 2 weeks until T-cell reconstitution as defined by cluster of differentiation 4 (CD4) > 200 cells/mm3. Median time to T-cell reconstitution was 6 months. | Up to one year post-transplant |
| Disease-free Survival With Correction of Disease at One Year Post Transplantation | Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation | 1 year post-transplantation |
| University of Wisconsin Paul P. Carbone Comprehensive Cancer Center |
| Madison |
| Wisconsin |
| 53792-6164 |
| United States |
| COMPLETED |
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| NOT COMPLETED |
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Thirty-five children undergoing allogeneic hemotopoietic stem cell transplants (HSCTs) for malignant and nonmalignant diseases; 12 with HLA-matched related donors (MRDs), 16 with 10 of 10 HLA allele-matched unrelated donors (MUDs), 7 with 9 of 10 allele MUDs.
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| ID | Title | Description |
|---|---|---|
| BG000 | Single Arm - Transplant Pre-conditioning Per Study Protocol | All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| 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 | Number of Participants Achieving Durable Engraftment (Presence of Donor Cells) at 6 Weeks Post Transplantation | Peripheral blood chimerism studies were performed by quantitative real time polymerase chain reaction (qPCR) evaluation of differential short tandem repeat DNA sequences | Participants evaluable for engraftment 6 weeks post-transplant; 1 patient died of transplant-related hemorrhage prior to 6 weeks and was not evaluated for this outcome | Posted | Number | participants | 6 weeks post-transplant |
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| Secondary | Treatment-related Mortality at 100 Days and 1 Year Post Transplantation | Posted | Number | participants | 100 days and 1 year |
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| Secondary | Toxicity Grade ≥ 3 From Start of Conditioning Through the First Year Post Transplantation | Posted | Number | participants | 1 year post-transplantation |
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| Secondary | Cytomegalovirus (CMV) Viral Infection and Disease Symptoms | polymerase chain reaction testing for presence of CMV weekly until at least day +100 then every 2 weeks until T-cell reconstitution as defined by cluster of differentiation 4 (CD4) > 200 cells/mm3. Median time to T-cell reconstitution was 6 months. | 4 participants were incapable of producing Ab or CMV testing result was indeterminate | Posted | Number | participants | Up to one year post-transplant |
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| Secondary | Disease-free Survival With Correction of Disease at One Year Post Transplantation | Patients deemed "alive and well" at follow-up timepoint later than 1-year post-transplantation | Posted | Number | participants | 1 year post-transplantation |
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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 | Single Arm - Transplant Pre-conditioning Per Study Protocol | All eligible patients received pre-transplant conditioning with Alemtuzumab, fludarabine and targeted busulfan followed by allogeneic transplant. The initial dose of busulfan was determined by performing PK (pharmacokinetics) analysis on a test dose of busulfan on the day prior to initiating conditioning. Based on the PK results a starting dose of busulfan was determined. A second PK study was done after the starting dose to ensure that the targeted dose was achieved. If it wasn't achieved, then a dose modification was made and a third PK study done. | 7 | 35 | 33 | 35 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| aGVHD (acute Graft-Versus-Host Disease) | General disorders | Systematic Assessment | acute Graft-Versus-Host Disease |
| |
| Respiratory distress associated with Cytomegalovirus infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | After 4th unrelated donor transplant (off study), patient developed respiratory distress that was associated with a CMV infection. Respiratory distress worsened in spite of maximal therapy. The parents elected to withdraw therapy and he died. |
| |
| Pancytopenia and splenomegaly | Blood and lymphatic system disorders | Non-systematic Assessment | Child presented with fever and pancytopenia, splenomegaly and was admitted for possible recurrent disease. |
| |
| Repiratory failure following ideopathic pneumonia syndrome | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Worsening respiratory status despite maximal support, at parent's request, patient was removed from mechanical ventilation, and the patient died quickly and peacefully. |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | Non-systematic Assessment | Sudden onset of thrombocytopenia of unknown etiology. |
| |
| Aspergillus pneumonia | Infections and infestations | Non-systematic Assessment | Patient admitted with cough and fever and diagnosed with Aspergillus pneumonia. |
| |
| Renal Failure | Renal and urinary disorders | Non-systematic Assessment | Patient developed renal failure and is required dialysis |
| |
| Graft rejection/failure | Blood and lymphatic system disorders | Systematic Assessment | initially, cells recovered normally with neutrophil count >500 by day +12 post-transplant. By day +20 they began a slow decline and by day +40 the neutrophil count was <500 with 99% host CD3+ (cluster of differentiation 3-positive) cells. |
| |
| Viral Encephalitis | Infections and infestations | Non-systematic Assessment |
| ||
| Massive intracranial bleed | Vascular disorders | Non-systematic Assessment | Child died from a massive intracranial bleed, probably due to Evan's syndrome and myeloablation; possible viral encephalitis possibly increased risk of intracranial hemorrhage. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mucositis (All grades) | Gastrointestinal disorders | Systematic Assessment | < Grade III - 17 participants; Grade III - 15 participants; Grade IV - 1 participant |
| |
| aGVHD | General disorders | Systematic Assessment | aGVHD < Grade IV |
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| cGVHD (Chronic graft-versus-host disease) | General disorders | Systematic Assessment |
| ||
| Infusion reaction to alemtuzumab | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Morton Cowan | University of California San Francisco | 4154762188 | mcowan@peds.ucsf.edu |
| ID | Term |
|---|---|
| C535982 | Congenital amegakaryocytic thrombocytopenia |
| D029503 | Anemia, Diamond-Blackfan |
| D007938 | Leukemia |
| D009190 | Myelodysplastic Syndromes |
| C537592 | Neutropenia, Severe Congenital, Autosomal Recessive 3 |
| D015466 | Leukemia, Myeloid, Chronic-Phase |
| ID | Term |
|---|---|
| D029502 | Anemia, Hypoplastic, Congenital |
| D000741 | Anemia, Aplastic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D012010 | Red-Cell Aplasia, Pure |
| D000080984 | Congenital Bone Marrow Failure Syndromes |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D015464 | Leukemia, Myelogenous, Chronic, BCR-ABL Positive |
| D007951 | Leukemia, Myeloid |
| D009196 | Myeloproliferative Disorders |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000074323 | Alemtuzumab |
| D002066 | Busulfan |
| D016572 | Cyclosporine |
| C042382 | fludarabine phosphate |
| D008727 | Methotrexate |
| D008775 | Methylprednisolone |
| D036102 | Peripheral Blood Stem Cell Transplantation |
| D036101 | Cord Blood Stem Cell Transplantation |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| 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 |
| D003524 | Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| 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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| Transplantation-related mortality 0-100 days |
|
| Transplantation-related mortality 100-365 days |
|
| Grade 3-4 acute Graft-Versus-Host Disease |
|
| Grade 3-4 mucositis |
|
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| Title | Denominators | Categories |
|---|
|