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Bone Marrow Cell Gene Transfer in Individuals With Fanconi Anemia

Primary Purpose

Fanconi Anemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Retrovirus Construct
Sponsored by
Boston Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fanconi Anemia

Eligibility Criteria

1 Year - 35 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: FA, as determined by a positive test for increased sensitivity to chromosomal breakage with mitomycin C or diepoxybutane FA complementation group A, as determined by somatic cell hybrids or molecular characterization; transduction of peripheral blood or bone marrow cells with the complementation group of specific retrovirus used in this study must demonstrate correction of mitomycin C sensitivity or cell cycle arrest Weighs at least 7.5 kg Normal cytogenetics on bone marrow within 3 months of study entry A minimum of 2 x 10(6) CD34+ cells/kg after CD34+ selection of the harvested bone marrow or mobilized peripheral blood product must be available to proceed with thaw (if cryopreserved) and transduction Human leukocyte antigen (HLA) typing with initial donor limited search results that indicate a potentially acceptable matched unrelated donor in the National Marrow Donor Program database Exclusion Criteria: Cancer Clonal cytogenetic abnormality on bone marrow or peripheral blood karyotype within 3 months of study entry Myelodysplastic syndrome based on the FAB classification including: Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) RAEB in transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML) (myelodysplastic changes in greater than two cell lines, refractory anemia alone, or aplastic anemia with dysplastic changes are permitted) Positive baseline screening result for both of the following: Detection of Fanconi A proviral sequences by polymerase chain reaction (PCR) analysis Detection of replication competent retrovirus by repeat testing by PCR of gibbon ape leukemia virus (GALV) envelope sequence or a positive S+L- assay Pregnant or breastfeeding; women of childbearing potential who are enrolled will be advised that the drug may cause birth defects and will be required to use an acceptable form of contraception Concurrent enrollment in any other study using an investigational agent, excluding androgens and thyroxine Physical or emotional status that would prevent informed consent, protocol compliance, or adequate follow-up with participant or legal guardian Participants for whom an acceptable HLA identical matched sibling donor (HLA A, B, DRB1; 6/6 match) has been identified (HLA typing of normal siblings must be documented)

Sites / Locations

  • Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single arm

Arm Description

Outcomes

Primary Outcome Measures

Safety of gene transfer methods
Short-term and long-term engraftment of gene-corrected autologous hematopoietic cells (all measured at Year 1)

Secondary Outcome Measures

Frequency and function of the integrated recombinant Fanconi vector
Efficiency of engraftment of multilineage gene corrected clones
Lineage contribution and longevity of molecularly distinguishable gene marked clones
Development of myelodysplastic syndrome or overt leukemia (all measured at Year 1)

Full Information

First Posted
January 4, 2006
Last Updated
June 21, 2017
Sponsor
Boston Children's Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Children's Hospital Medical Center, Cincinnati
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1. Study Identification

Unique Protocol Identification Number
NCT00272857
Brief Title
Bone Marrow Cell Gene Transfer in Individuals With Fanconi Anemia
Official Title
Gene Transfer From Patients With Fanconi Anemia, Genotype A: A Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
August 2004 (undefined)
Primary Completion Date
October 2007 (Actual)
Study Completion Date
October 2007 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston Children's Hospital
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Children's Hospital Medical Center, Cincinnati

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Fanconi anemia (FA) is a disease that affects an individual's bone marrow. It is caused by a defective gene in the bone marrow cells that produce various types of blood cells. Individuals with FA may experience fatigue, bleeding, and increased infections. The purpose of this study is to evaluate the safety and effectiveness of a gene transfer procedure in generating new, healthy cells in individuals with FA.
Detailed Description
FA is a rare, inherited disease that is caused by a gene defect and that primarily affects an individual's bone marrow, resulting in decreased production of blood cells. The lack of white blood cells affects an individual's ability to fight infections, the lack of platelets may result in bleeding, and the lack of red blood cells usually leads to anemia. FA is typically diagnosed in childhood, and there is a high fatality rate. Bone marrow transplants are one common treatment for FA. However, there are many risks associated with transplantation, including rejection of the transplanted cells and graft-versus-host disease, a serious side effect in which donor cells attack the recipient's tissues. This study will use an experimental gene transfer procedure performed in a laboratory to insert a new FA gene into the participant's bone marrow cells. The gene-corrected bone marrow cells will then be re-infused into the participant and participants will be observed for successful gene transfer. The purpose of this study is to evaluate the safety and effectiveness of the FA gene transfer procedure and to determine the ability of the gene-corrected cells at generating new, healthy blood cells in individuals with FA. This study will enroll individuals with FA. Participants will be required to have the initial bone marrow transfer procedure performed at Cincinnati Children's Hospital, but will be allowed to see their own doctor for the majority of study visits. Participants will first attend a screening visit, which will include a physical exam, blood draw for laboratory testing, and a bone marrow biopsy. Bone marrow cells will be collected from eligible participants and sent to a laboratory for the FA gene transfer procedure. Several days later, the gene-corrected cells will be re-infused back into the participants via an intravenous catheter. Side effects will be closely monitored for 12 hours following the procedure and participants may be required to spend an overnight in the hospital. Following discharge from the hospital, participants will be required to stay in the Cincinnati area for 3 days to undergo daily evaluations and physical examinations. Participants will continue to be followed very closely for the first year after cell re-infusion. Study visits will be held weekly for the first 3 weeks, and then every 3 months for the remainder of the year. Visits will include physical examinations, blood collection, and liver function testing. Bone marrow testing will occur at Months 3, 6, and 12. Follow-up visits will occur yearly for up to 15 years and will include blood collection, a physical exam, and review of medical history.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fanconi Anemia

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Single arm
Arm Type
Experimental
Intervention Type
Genetic
Intervention Name(s)
Retrovirus Construct
Intervention Description
This study will use an experimental gene transfer procedure performed in a laboratory to insert a new FA gene into the participant's bone marrow cells. The gene-corrected bone marrow cells will then be re-infused into the participant and participants will be observed for successful gene transfer
Primary Outcome Measure Information:
Title
Safety of gene transfer methods
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer
Title
Short-term and long-term engraftment of gene-corrected autologous hematopoietic cells (all measured at Year 1)
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer
Secondary Outcome Measure Information:
Title
Frequency and function of the integrated recombinant Fanconi vector
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer
Title
Efficiency of engraftment of multilineage gene corrected clones
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer
Title
Lineage contribution and longevity of molecularly distinguishable gene marked clones
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer
Title
Development of myelodysplastic syndrome or overt leukemia (all measured at Year 1)
Time Frame
3months, 6 months and yearly up to 15 years post gene transfer

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: FA, as determined by a positive test for increased sensitivity to chromosomal breakage with mitomycin C or diepoxybutane FA complementation group A, as determined by somatic cell hybrids or molecular characterization; transduction of peripheral blood or bone marrow cells with the complementation group of specific retrovirus used in this study must demonstrate correction of mitomycin C sensitivity or cell cycle arrest Weighs at least 7.5 kg Normal cytogenetics on bone marrow within 3 months of study entry A minimum of 2 x 10(6) CD34+ cells/kg after CD34+ selection of the harvested bone marrow or mobilized peripheral blood product must be available to proceed with thaw (if cryopreserved) and transduction Human leukocyte antigen (HLA) typing with initial donor limited search results that indicate a potentially acceptable matched unrelated donor in the National Marrow Donor Program database Exclusion Criteria: Cancer Clonal cytogenetic abnormality on bone marrow or peripheral blood karyotype within 3 months of study entry Myelodysplastic syndrome based on the FAB classification including: Refractory anemia with ringed sideroblasts (RARS) Refractory anemia with excess blasts (RAEB) RAEB in transformation (RAEB-T) Chronic myelomonocytic leukemia (CMML) (myelodysplastic changes in greater than two cell lines, refractory anemia alone, or aplastic anemia with dysplastic changes are permitted) Positive baseline screening result for both of the following: Detection of Fanconi A proviral sequences by polymerase chain reaction (PCR) analysis Detection of replication competent retrovirus by repeat testing by PCR of gibbon ape leukemia virus (GALV) envelope sequence or a positive S+L- assay Pregnant or breastfeeding; women of childbearing potential who are enrolled will be advised that the drug may cause birth defects and will be required to use an acceptable form of contraception Concurrent enrollment in any other study using an investigational agent, excluding androgens and thyroxine Physical or emotional status that would prevent informed consent, protocol compliance, or adequate follow-up with participant or legal guardian Participants for whom an acceptable HLA identical matched sibling donor (HLA A, B, DRB1; 6/6 match) has been identified (HLA typing of normal siblings must be documented)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Franklin O. Smith, MD
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
17164793
Citation
Kelly PF, Radtke S, von Kalle C, Balcik B, Bohn K, Mueller R, Schuesler T, Haren M, Reeves L, Cancelas JA, Leemhuis T, Harris R, Auerbach AD, Smith FO, Davies SM, Williams DA. Stem cell collection and gene transfer in Fanconi anemia. Mol Ther. 2007 Jan;15(1):211-9. doi: 10.1038/sj.mt.6300033.
Results Reference
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Bone Marrow Cell Gene Transfer in Individuals With Fanconi Anemia

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