Total Body Irradiation With Fludarabine Followed by Combined Umbilical Cord Blood (UCB) Transplants - Full Text View

Sponsored by:	Duke University
Information provided by:	Duke University
ClinicalTrials.gov Identifier:	NCT00606437

Purpose

Results to date of umbilical cord blood transplantation in adult and fully mature adolescent patients are inferior to what is seen in children, due to a lower stem cell dosage in adults and a more toxic conditioning regimen. This phase 1 protocol will use a potentially less toxic bone marrow conditioning regimen, followed by infusion of a combined umbilical cord blood graft that will provide the patient with a higher stem cell dose than can be given with a single umbilical cord blood infusion. The subjects will be conditioned with a total body irradiation (TBI) 13.5 Gy and fludarabine. Following conditioning, up to two unrelated, partially matched umbilical cord blood grafts will be infused that will provide a minimum nucleated cell dose of 3 x 10e7/kg . The primary objective of this study is to measure the frequency of treatment-related toxicity and engraftment.

Condition	Intervention	Phase
Lymphoma Myeloma Leukemia Myelodysplasia Solid Tumors Hodgkin's Disease Myelofibrosis	Procedure: Total Body Irradiation with Fludarabine in UCB Transplants	Phase I

Study Type:	Interventional
Study Design:	Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title:	Total Body Irradiation With Fludarabine Conditioning Followed by Transplantation With Combined Umbilical Cord Blood Grafts

Resource links provided by NLM:

MedlinePlus related topics: Cancer Hodgkin Disease Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood Lymphoma Radiation Therapy Spleen Diseases

Drug Information available for: Fludarabine Fludarabine monophosphate

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:

The primary objective will be to measure the time to and rate of hematologic engraftment following transplant and the frequency of treatment-related mortality. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

The secondary objective will be to estimate the proportion of patients developing acute and chronic graft-versus-host disease, 100 day treatment-related mortality, and to measure disease-free survival. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
The tertiary objective will be to measure the time to immunologic reconstitution as defined by normal numbers of T and B cells, normal T-cell proliferative responses, normal natural killer (NK) cell function, and normal immunoglobulin synthesis. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	24
Study Start Date:	September 2005
Estimated Study Completion Date:	September 2011
Estimated Primary Completion Date:	September 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
I: Experimental Total Body Irradiation (TBI)/Flu Conditioning followed by combined UCB	Procedure: Total Body Irradiation with Fludarabine in UCB Transplants Administration of the preparative regimen, infusion of the stem cell graft, inpatient care during the immediate post-transplant period and outpatient follow-up for the first 3 months after transplant and at 6, 12, 24 and 36 months. Patients will have human leukocyte antigen (HLA) serologic typing and DNA typing. Bags of UCB are thawed, and diluted by 1:1 volume using a 5% albumin/dextran solution. The thawed and diluted umbilical cord blood unit (UCBU) is next weighed and centrifuged. Specimens are obtained for cell count and viability, culture, clonogenic assays, and phenotype. The UCB is infused at a rate of 1-3 ml/min. Furosemide (0.5-1.0 mg/kg/dose) may be given if volume overload or decreased urine output occurs. Each UCB infusion shall be tested for sterility, CFU content, number of CD34+ cells, cell count and viability.

Arms

Assigned Interventions

I: Experimental

Total Body Irradiation (TBI)/Flu Conditioning followed by combined UCB

Procedure: Total Body Irradiation with Fludarabine in UCB Transplants

Administration of the preparative regimen, infusion of the stem cell graft, inpatient care during the immediate post-transplant period and outpatient follow-up for the first 3 months after transplant and at 6, 12, 24 and 36 months. Patients will have human leukocyte antigen (HLA) serologic typing and DNA typing. Bags of UCB are thawed, and diluted by 1:1 volume using a 5% albumin/dextran solution. The thawed and diluted umbilical cord blood unit (UCBU) is next weighed and centrifuged. Specimens are obtained for cell count and viability, culture, clonogenic assays, and phenotype. The UCB is infused at a rate of 1-3 ml/min. Furosemide (0.5-1.0 mg/kg/dose) may be given if volume overload or decreased urine output occurs. Each UCB infusion shall be tested for sterility, CFU content, number of CD34+ cells, cell count and viability.

Detailed Description:

Results to date of umbilical cord blood transplantation in adult and fully mature adolescent patients are inferior to what is seen in children. There are two reasons for this. First is that the stem cell dose, measured in nucleated cells/kg body weight, is considerably lower due to the size of the recipient. This results in a higher incidence of graft failure, delayed engraftment, and impaired immune reconstitution. Multiple studies have suggested that a nucleated cell dose below 1.5 to 2 x 107/kg results in an unacceptably high risk for graft failure. Only a minority of adult patients will have a suitably matched umbilical cord blood unit that contains more than 1.5 x 107 nucleated cells/kg. The second reason for inferior outcome of umbilical cord blood transplantation in adult patients is that in comparison to children, the conventional myeloablative bone marrow conditioning regimens are more toxic. This phase 1 protocol will use a potentially less toxic bone marrow conditioning regimen, followed by infusion of a combined umbilical cord blood graft that will provide the patient with a higher stem cell dose than can be given with a single umbilical cord blood infusion. The subjects will be conditioned with a TBI 13.5 Gy and fludarabine. Fludarabine pharmacokinetics will be measured and correlated with the kinetics of donor cell engraftment as well frequency of treatment-related toxicity. Following conditioning, up to two unrelated, partially matched umbilical cord blood grafts will be infused that will provide a minimum nucleated cell dose of 3 x 10e7/kg. The primary objective of this study is to measure the frequency of treatment-related toxicity and engraftment.

Eligibility

Ages Eligible for Study:	14 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age 14 to 65 years.
Available cord blood graft.
Patients with high risk ALL in first complete remission, with high risk being defined by the presence of t(4;11), t(9;22) or t(1;19) or patients presenting with extreme hyperleukocytosis (WBC > 500,000/ul) or partial remission after induction therapy.
Adult patients with acute non-lymphocytic leukemia (ANLL) in first complete remission with high-risk cytogenetics (monosomy chromosome 5 or 7, del (5q), abn (3q26), complex karyotypic abnormalities) or failure to achieve complete remission after standard induction therapy.
All patients with ALL or ANLL in second or subsequent remission or partial remission.
All patients with CML in chronic (failed interferon and/or Gleevec) or accelerated phase.
Patients with myelodysplastic syndrome with International Prognostic Scoring System (IPSS) risk category of INT-1 or greater.
Patients with severe aplastic anemia must have failed immunosuppressive therapy such as cyclosporine plus anti-thymocyte globulin.
Non-Hodgkin's lymphoma or Hodgkin's disease:
- High risk disease in first complete or partial remission
- Chemotherapy-resistant relapse
- Second or subsequent relapse or remission
Myelofibrosis with myeloid metaplasia.
High risk, congenital immunodeficiency disorders resulting in recurrent (> 3 episodes) life-threatening infection, known to be curable with allogeneic stem cell transplantation (to include, but not limited to; severe combined immunodeficiency disorder, combined immunodeficiency disease, Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, hemophagocytic lymphohistiocytosis).
Patients with a history of CNS disease must have been treated and have no active CNS disease at the time of protocol treatment.
ECOG performance status < or equal to 2.
Patients must have adequate function of other organ systems as measured by:
- Creatinine clearance (by Cockcroft Gault equation) > or equal to 30 ml/min. Hepatic transaminases (ALT/AST) < or equal to 4 x normal, bilirubin < or equal to 2.0 mg/dl
- Pulmonary function tests demonstrating FVC and FEV1 of > or equal to 50% of predicted for age and DLCO
  - or equal to 50% of predicted
- Ejection fraction of > or equal to 45% by echocardiogram, radionuclide scan or cardiac MRI
Patients must be HIV negative.
They do not have an HLA-ABC/DR identical related bone marrow or UCB donor.
They do NOT have a 5/6 antigen matched related bone marrow or UCB donor.
Their condition precludes waiting to search and find a donor in the National Marrow Donor Registry or an 8/8 (HLA-A, B, C, DRB1) antigen by high resolution (allele-level) typing matched unrelated donor was not found.
Patients must not be pregnant.

Exclusion Criteria:

Patients that have circulating antibodies specific for donor major histocompatibility antigens (as determined by panel of reactive antibody assay).
Patients with progressive ANLL or ALL following second or third-line treatment regimens.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00606437

Locations

United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Investigators

Principal Investigator:

Mitchell Horwitz, MD

Duke University Health System

More Information

No publications provided

Responsible Party:	Duke University Health System, Department of Medicine, Cell Therapy Div. ( Mitchell Horwitz, MD )
Study ID Numbers:	00009529
Study First Received:	January 7, 2008
Last Updated:	August 4, 2009
ClinicalTrials.gov Identifier:	NCT00606437 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by Duke University:

Umbilical Cord Blood Graft
Stem Cell Transplantation

Study placed in the following topic categories:

Antimetabolites
Precancerous Conditions
Immunologic Factors
Furosemide
Leukemia
Preleukemia
Metaplasia
Hodgkin Disease
Lymphoma
Dextrans
Myelofibrosis
Immunoproliferative Disorders
Hematologic Diseases

Hodgkin Lymphoma, Adult
Myelodysplastic Syndromes
Myeloproliferative Disorders
Hodgkin's Disease
Fludarabine monophosphate
Immunosuppressive Agents
Multiple Myeloma
Myeloid Metaplasia
Lymphatic Diseases
Fludarabine
Bone Marrow Diseases
Lymphoproliferative Disorders
Neoplasms, Plasma Cell

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Precancerous Conditions
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Leukemia
Preleukemia
Therapeutic Uses
Lymphoma
Hodgkin Disease
Myelofibrosis
Neoplasms by Histologic Type
Immunoproliferative Disorders

Immune System Diseases
Hematologic Diseases
Myelodysplastic Syndromes
Myeloproliferative Disorders
Fludarabine monophosphate
Immunosuppressive Agents
Pharmacologic Actions
Myeloid Metaplasia
Lymphatic Diseases
Neoplasms
Fludarabine
Bone Marrow Diseases
Lymphoproliferative Disorders
Splenic Diseases

ClinicalTrials.gov processed this record on September 03, 2009