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Total Body Irradiation With Fludarabine Followed by Combined Umbilical Cord Blood (UCB) Transplants

Primary Purpose

Lymphoma, Myeloma, Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Total Body Irradiation with Fludarabine in UCB Transplants
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring Umbilical Cord Blood Graft, Stem Cell Transplantation

Eligibility Criteria

14 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Duke University Health System

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

I

Arm Description

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

Outcomes

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.

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.
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.

Full Information

First Posted
January 7, 2008
Last Updated
May 15, 2014
Sponsor
Duke University
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1. Study Identification

Unique Protocol Identification Number
NCT00606437
Brief Title
Total Body Irradiation With Fludarabine Followed by Combined Umbilical Cord Blood (UCB) Transplants
Official Title
Total Body Irradiation With Fludarabine Conditioning Followed by Transplantation With Combined Umbilical Cord Blood Grafts
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
September 2005 (undefined)
Primary Completion Date
February 2014 (Actual)
Study Completion Date
February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma, Myeloma, Leukemia, Myelodysplasia, Solid Tumors, Hodgkin's Disease, Myelofibrosis
Keywords
Umbilical Cord Blood Graft, Stem Cell Transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
I
Arm Type
Experimental
Arm Description
Total Body Irradiation (TBI)/Flu Conditioning followed by combined UCB
Intervention Type
Procedure
Intervention Name(s)
Total Body Irradiation with Fludarabine in UCB Transplants
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mitchell Horwitz, MD
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Health System
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

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Total Body Irradiation With Fludarabine Followed by Combined Umbilical Cord Blood (UCB) Transplants

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