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Gene Therapy for Fanconi Anemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01331018
First received: March 16, 2011
Last updated: September 11, 2014
Last verified: September 2014

March 16, 2011
September 11, 2014
February 2012
December 2017   (final data collection date for primary outcome measure)
  • Hematological and non-hematological organ toxicity [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Adverse events will be graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.
  • Development of insertional mutagenesis or hematologic malignancy [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Adverse events will be graded by CTCAE, version 4.
  • Development of replication competent lentivirus [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
    Adverse events will be graded by CTCAE, version 4.
Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Fifteen years ] [ Designated as safety issue: Yes ]
Monitoring of adverse events by CTCAE v.3 criteria. Laboratory tests to include complete blood count, chemistry metabolic panel and liver function tests. Research testing will include monitoring of dominant clones by insertion site analysis and monitoring for replication competent lentivirus. Research testing to be performed at 3 months, 6 months, 12 months post infusion of modified cells, and annually thereafter. Clinical laboratory studies to be performed more frequently during the first 3 months post infusion.
Complete list of historical versions of study NCT01331018 on ClinicalTrials.gov Archive Site
  • Transduction efficiency [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction (PCR).
  • Improved blood counts [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    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 (DNA) crosslinking agent, mitomycin C.
  • Total Number of CD34+ Cells Mobilized per Kilogram Weight after G-CSF with Plerixafor (latter if age 18 or older) [ Time Frame: 5 days ] [ Designated as safety issue: No ]
    Total cell CD34+ cell count to be determined after completion of leukapheresis procedure.
  • Transduction efficiency [ Time Frame: 6th day ] [ Designated as safety issue: No ]
    After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.
  • Percent of transduced cells in blood and bone marrow [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Blood and bone marrow samples will be assayed by real time quantitative polymerase chain reaction at intervals from weekly to quarterly during the first year after infusion.
  • Improved blood counts [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.
  • Mitomycin C resistance in blood and bone marrow cells [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Blood and bone marrow cells will be assayed for viability of cultured cells and hematopoietic colonies in the presence of the chemotherapy drug and DNA crosslinking agent, mitomycin C.
Not Provided
Not Provided
 
Gene Therapy for Fanconi Anemia
Gene Transfer for Patients With Fanconi Anemia Complementation Group A (FANCA)

This pilot 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.

PRIMARY OBJECTIVES:

I. To determine the safety of lentiviral gene transfer for patients with Fanconi anemia complementation group A (FANCA).

SECONDARY OBJECTIVES:

I. To determine the transduction efficiency for human FA patient hematopoietic progenitor cells transduced with a clinical grade lentiviral vector encoding the gene for Fanconi anemia complementation group A.

II. To determine if the clinical grade transduction will result in phenotypic correction of gene modified cells by in vitro assays.

III. To determine if infusion of FANCA gene-modified cells will result in engraftment and improvement in blood counts in FA patients.

OUTLINE:

BONE MARROW HARVEST FOR CELL COLLECTION: Patients undergo bone marrow harvest for collection of stem/progenitor cells on days -2 and -1.

REINFUSION: Patients undergo reinfusion of genetically modified hematopoietic progenitor cells on day 0.

After completion of study treatment, patients are followed up periodically for 15 years.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Fanconi Anemia
  • Procedure: harvest procedure
    Undergo bone marrow harvest
    Other Name: harvest
  • Biological: genetically engineered lymphocyte therapy
    Undergo infusion of genetically modified hematopoietic progenitor cell therapy
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (genetically engineered lymphocyte therapy)

BONE MARROW HARVEST FOR CELL COLLECTION: Patients undergo bone marrow harvest for collection of stem/progenitor cells on days -2 and -1.

REINFUSION: Patients undergo reinfusion of genetically modified hematopoietic progenitor cells on day 0.

Interventions:
  • Procedure: harvest procedure
  • Biological: genetically engineered lymphocyte therapy
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
10
Not Provided
December 2017   (final data collection date for primary outcome measure)

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, or acquisition of mitomycin C resistance after in vitro lentiviral transduction with a vector bearing the complementary deoxyribonucleic acid (cDNA) for Fanconi complementation group A
  • 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%
  • 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 Heart Association [NYHA] 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
Both
4 Years and older
No
United States
 
NCT01331018
2097.00, NCI-2011-00202, 2097.00, P30CA015704
Yes
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Cancer Institute (NCI)
Principal Investigator: Pamela Becker Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP