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Gene Therapy for Fanconi Anemia

Primary Purpose

Fanconi Anemia

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Bone Marrow Aspiration
Filgrastim
Genetically Engineered Hematopoietic Stem Progenitor Cells
Laboratory Biomarker Analysis
Leukapheresis
Methylprednisolone
Plerixafor
Prednisone
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fanconi Anemia

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • FA demonstrated by a positive test for increased sensitivity to chromosomal breakage with mitomycin C or diepoxybutane performed by a Clinical Laboratory Improvement Amendments (CLIA) or College of American Pathologists (CAP) approved laboratory
  • FA complementation group A as determined by somatic cell hybrids, molecular characterization, western blot analysis, acquisition of mitomycin C resistance after in vitro lentiviral transduction with a vector bearing the complementary deoxyribonucleic acid (cDNA) for Fanconi complementation group A, or other clinically certified method of complementation group analysis
  • Bone marrow analysis demonstrating normal cytogenetics, and no more than 5% of cells with a single clonal abnormality by fluorescence in situ hybridization (FISH) for myelodysplastic syndrome (MDS) panel within 3 months of stem cell collection
  • Signed informed consent by the patient or legally authorized representative
  • Absolute neutrophil count >= 0.5 x 10^9/L
  • Hemoglobin >= 8 g/dL
  • Platelet count >= 20 x 10^9/L and able to achieve a platelet count of >= 50 x 10^9/L with transfusion support
  • Adequate hepatic function with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
  • Adequate renal function with creatinine (Cre) =< 1.5; if greater, then glomerular filtration rate (GFR) > 60 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation
  • Adequate pulmonary function with corrected diffusion capacity of carbon monoxide (DLCO) > 50% in those for whom this study can be performed
  • For subjects < 17 years of age, Modified Lansky Play-Performance Score of >= 70%; for subjects 17 and older, Karnofsky score of >= 70%

Exclusion Criteria:

  • Non-hematopoietic malignancy where the expected survival is less than 2 years
  • Myelodysplastic syndrome as defined by World Health Organization (WHO) criteria
  • Acute myeloid leukemia as defined by WHO criteria
  • Pregnancy or lactation; females of childbearing potential and males who are admitted to the study will be advised that the study procedures and study drugs may be teratogenic, and they will be required to take adequate measures to prevent conception for the duration of the study
  • Concurrent enrollment in any other study using an investigational drug
  • Physical or emotional status that would prevent informed consent, protocol compliance, or adequate follow-up
  • Patients for whom an human leukocyte antigen (HLA) matched sibling donor bone marrow transplant is being actively pursued will not be eligible for study until it is determined that no sibling donor is available or that a stem cell transplant is not feasible during the time the patient might be on study

    • No patient will be included in this study as an alternative to a clinically indicated HLA matched sibling donor stem cell transplant
    • If an HLA matched sibling donor is identified, but stem cell or marrow collection is not feasible (e.g., donor is in utero, is a newborn from whom cord blood was not collected, or is unable to undergo a donation procedure because of ill health), a patient may be included in the study at the discretion of the investigators
  • Significant associated diseases including documented human immunodeficiency virus (HIV) infection, uncontrolled hypertension (diastolic blood pressures > 95%ile for age), unstable angina, congestive heart failure (> New York [NY] class II), poorly controlled diabetes (hemoglobin A1c [Hgb A1c] > 7%), coronary angioplasty within 6 months, myocardial infarction within the last 6 months, or uncontrolled atrial or ventricular cardiac arrhythmia, abnormal coagulation, persistent abnormal urinalysis reflecting intrinsic renal disease
  • Active ongoing viral, bacterial, or fungal infection

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (hematopoietic stem progenitor cells)

Arm Description

STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim SC BID for up to 6 days (on days 1-6 of mobilization). Patients receive plerixafor SC QD on days 4-6 of mobilization. PBSC count will be checked daily starting on day 4 of mobilization. Patients who have a PBSC count of >= 5 CD34+ cells/mcL will undergo up to 2 apheresis collections on consecutive days. BONE MARROW HARVEST FOR CELL COLLECTION: Patients with inadequate PBSC counts undergo bone marrow harvest for collection of stem/progenitor cells. REINFUSION: Patients receive methylprednisolone IV or prednisone PO on days -1 to 7 followed by a rapid taper over approximately 1 week and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0.

Outcomes

Primary Outcome Measures

Toxicity of gene transfer
Adverse events will be graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.
Hematological and non-hematological organ toxicity
Adverse events will be graded by CTCAE, version 4.
Development of insertional mutagenesis or hematologic malignancy
Adverse events will be graded by CTCAE, version 4.
Development of replication competent lentivirus
Adverse events will be graded by CTCAE, version 4.

Secondary Outcome Measures

Efficacy of G-CSF and plerixafor mobilization in Fanconi anemia (FA) patients
Efficacy of lineage depletion of bone marrow or mobilized cell product
Transduction efficiency
After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.
Detectable levels of transduced cells in blood and marrow
Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction.
Improved blood counts
Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.
Demonstrable functional expression by growth of recipient cells in mitomycin C
Blood and bone marrow cells will be assayed for viability of cultured cells and hematopoietic colonies in the presence of the chemotherapy drug and deoxyribonucleic acid crosslinking agent, mitomycin C.

Full Information

First Posted
March 16, 2011
Last Updated
July 10, 2023
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Rocket Pharma Limited
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1. Study Identification

Unique Protocol Identification Number
NCT01331018
Brief Title
Gene Therapy for Fanconi Anemia
Official Title
Gene Transfer for Patients With Fanconi Anemia Complementation Group A (FANCA)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 22, 2012 (Actual)
Primary Completion Date
July 17, 2032 (Anticipated)
Study Completion Date
July 17, 2032 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Rocket Pharma Limited

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This clinical trial will access the toxicity and efficacy of infusion of gene modified cells for patients with Fanconi anemia (FA). Infusion of autologous patient blood stem cells that have been corrected in the laboratory by introduction of the normal gene may improve blood counts in patients with FA.
Detailed Description
OUTLINE: STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim subcutaneously (SC) twice daily (BID) for up to 6 days (on days 1-6 of mobilization). Patients receive plerixafor SC once daily (QD) on days 4-6 of mobilization. Peripheral blood stem cell (PBSC) count will be checked daily starting on day 4 of mobilization. Patients who have a PBSC count of >= 5 CD34+ cells/mcL will undergo up to 2 apheresis collections on consecutive days. BONE MARROW HARVEST FOR CELL COLLECTION: Patients with inadequate PBSC counts undergo bone marrow harvest for collection of stem/progenitor cells. REINFUSION: Patients receive methylprednisolone intravenously (IV) or prednisone orally (PO) on days -1 to 7 followed by a rapid taper over approximately 1 week and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0. After completion of study treatment, patients are followed up periodically for 15 years.

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
Treatment (hematopoietic stem progenitor cells)
Arm Type
Experimental
Arm Description
STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim SC BID for up to 6 days (on days 1-6 of mobilization). Patients receive plerixafor SC QD on days 4-6 of mobilization. PBSC count will be checked daily starting on day 4 of mobilization. Patients who have a PBSC count of >= 5 CD34+ cells/mcL will undergo up to 2 apheresis collections on consecutive days. BONE MARROW HARVEST FOR CELL COLLECTION: Patients with inadequate PBSC counts undergo bone marrow harvest for collection of stem/progenitor cells. REINFUSION: Patients receive methylprednisolone IV or prednisone PO on days -1 to 7 followed by a rapid taper over approximately 1 week and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0.
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Aspiration
Intervention Description
Undergo bone marrow harvest
Intervention Type
Biological
Intervention Name(s)
Filgrastim
Other Intervention Name(s)
FILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim
Intervention Description
Given SC
Intervention Type
Biological
Intervention Name(s)
Genetically Engineered Hematopoietic Stem Progenitor Cells
Other Intervention Name(s)
Genetically Engineered HSPCs
Intervention Description
Undergo infusion of genetically modified hematopoietic progenitor cell therapy
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Leukapheresis
Other Intervention Name(s)
Leukocytopheresis, Therapeutic Leukopheresis
Intervention Description
Undergo leukapheresis
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Other Intervention Name(s)
Adlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone, Firmacort, Medlone 21, Medrate, Medrol, Medrol Veriderm, Medrone, Mega-Star, Meprolone, Methylprednisolonum, Metilbetasone Solubile, Metrocort, Metypresol, Metysolon, Predni-M-Tablinen, Prednilen, Radilem, Sieropresol, Solpredone, Summicort, Urbason, Veriderm Medrol, Wyacort
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Plerixafor
Other Intervention Name(s)
AMD 3100, JM-3100, Mozobil, SDZ SID 791
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisonum, Prednitone, Promifen, Servisone, SK-Prednisone
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Toxicity of gene transfer
Description
Adverse events will be graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.
Time Frame
Up to 15 years
Title
Hematological and non-hematological organ toxicity
Description
Adverse events will be graded by CTCAE, version 4.
Time Frame
Up to 15 years
Title
Development of insertional mutagenesis or hematologic malignancy
Description
Adverse events will be graded by CTCAE, version 4.
Time Frame
Up to 15 years
Title
Development of replication competent lentivirus
Description
Adverse events will be graded by CTCAE, version 4.
Time Frame
Up to 15 years
Secondary Outcome Measure Information:
Title
Efficacy of G-CSF and plerixafor mobilization in Fanconi anemia (FA) patients
Time Frame
Up to 6 days
Title
Efficacy of lineage depletion of bone marrow or mobilized cell product
Time Frame
Up to 15 years
Title
Transduction efficiency
Description
After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.
Time Frame
Day 0
Title
Detectable levels of transduced cells in blood and marrow
Description
Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction.
Time Frame
Up to 1 year
Title
Improved blood counts
Description
Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.
Time Frame
Up to 15 years
Title
Demonstrable functional expression by growth of recipient cells in mitomycin C
Description
Blood and bone marrow cells will be assayed for viability of cultured cells and hematopoietic colonies in the presence of the chemotherapy drug and deoxyribonucleic acid crosslinking agent, mitomycin C.
Time Frame
3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: FA demonstrated by a positive test for increased sensitivity to chromosomal breakage with mitomycin C or diepoxybutane performed by a Clinical Laboratory Improvement Amendments (CLIA) or College of American Pathologists (CAP) approved laboratory FA complementation group A as determined by somatic cell hybrids, molecular characterization, western blot analysis, acquisition of mitomycin C resistance after in vitro lentiviral transduction with a vector bearing the complementary deoxyribonucleic acid (cDNA) for Fanconi complementation group A, or other clinically certified method of complementation group analysis Bone marrow analysis demonstrating normal cytogenetics, and no more than 5% of cells with a single clonal abnormality by fluorescence in situ hybridization (FISH) for myelodysplastic syndrome (MDS) panel within 3 months of stem cell collection Signed informed consent by the patient or legally authorized representative Absolute neutrophil count >= 0.5 x 10^9/L Hemoglobin >= 8 g/dL Platelet count >= 20 x 10^9/L and able to achieve a platelet count of >= 50 x 10^9/L with transfusion support Adequate hepatic function with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN) Adequate renal function with creatinine (Cre) =< 1.5; if greater, then glomerular filtration rate (GFR) > 60 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation Adequate pulmonary function with corrected diffusion capacity of carbon monoxide (DLCO) > 50% in those for whom this study can be performed For subjects < 17 years of age, Modified Lansky Play-Performance Score of >= 70%; for subjects 17 and older, Karnofsky score of >= 70% Exclusion Criteria: Non-hematopoietic malignancy where the expected survival is less than 2 years Myelodysplastic syndrome as defined by World Health Organization (WHO) criteria Acute myeloid leukemia as defined by WHO criteria Pregnancy or lactation; females of childbearing potential and males who are admitted to the study will be advised that the study procedures and study drugs may be teratogenic, and they will be required to take adequate measures to prevent conception for the duration of the study Concurrent enrollment in any other study using an investigational drug Physical or emotional status that would prevent informed consent, protocol compliance, or adequate follow-up Patients for whom an human leukocyte antigen (HLA) matched sibling donor bone marrow transplant is being actively pursued will not be eligible for study until it is determined that no sibling donor is available or that a stem cell transplant is not feasible during the time the patient might be on study No patient will be included in this study as an alternative to a clinically indicated HLA matched sibling donor stem cell transplant If an HLA matched sibling donor is identified, but stem cell or marrow collection is not feasible (e.g., donor is in utero, is a newborn from whom cord blood was not collected, or is unable to undergo a donation procedure because of ill health), a patient may be included in the study at the discretion of the investigators Significant associated diseases including documented human immunodeficiency virus (HIV) infection, uncontrolled hypertension (diastolic blood pressures > 95%ile for age), unstable angina, congestive heart failure (> New York [NY] class II), poorly controlled diabetes (hemoglobin A1c [Hgb A1c] > 7%), coronary angioplasty within 6 months, myocardial infarction within the last 6 months, or uncontrolled atrial or ventricular cardiac arrhythmia, abnormal coagulation, persistent abnormal urinalysis reflecting intrinsic renal disease Active ongoing viral, bacterial, or fungal infection
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hans-Peter Kiem
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Gene Therapy for Fanconi Anemia

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