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Gene Therapy for Fanconi Anemia

This study is currently recruiting participants.
Verified May 2017 by Fred Hutchinson Cancer Research Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT01331018
First Posted: April 7, 2011
Last Update Posted: May 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Rocket Pharma Limited
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
  Purpose
This pilot 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.

Condition Intervention Phase
Fanconi Anemia Procedure: Bone Marrow Aspiration Biological: Filgrastim Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells Other: Laboratory Biomarker Analysis Drug: Methylprednisolone Drug: Plerixafor Drug: Prednisone Procedure: Leukapheresis Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gene Transfer for Patients With Fanconi Anemia Complementation Group A (FANCA)

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Development of insertional mutagenesis or hematologic malignancy [ Time Frame: Up to 15 years ]
    Adverse events will be graded by CTCAE, version 4.

  • Development of replication competent lentivirus [ Time Frame: Up to 15 years ]
    Adverse events will be graded by CTCAE, version 4.

  • Hematological and non-hematological organ toxicity [ Time Frame: Up to 15 years ]
    Adverse events will be graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.


Secondary Outcome Measures:
  • Demonstrable functional expression by growth of recipient cells in mitomycin C [ Time Frame: 3 months ]
    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.

  • Detectable levels of transduced cells in blood and marrow [ Time Frame: Up to 1 year ]
    Blood and bone marrow samples will be assayed by real-time quantitative polymerase chain reaction.

  • Efficacy of G-CSF and plerixafor mobilization in FA patients [ Time Frame: Up to 6 days ]
  • Efficacy of lineage depletion of bone marrow or mobilized cell product [ Time Frame: Up to 15 years ]
  • Improved blood counts [ Time Frame: Up to 15 years ]
    Complete blood counts will be monitored, initially weekly, then monthly during the first year, then quarterly during the 2nd year after infusion.

  • Transduction efficiency [ Time Frame: Day 0 ]
    After completion of lentiviral transduction, the percent gene modified cells will be determined by molecular studies.


Estimated Enrollment: 10
Actual Study Start Date: February 22, 2012
Estimated Primary Completion Date: December 2027 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (hematopoietic stem progenitor cells)

STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim SC BID on days 1-6 of mobilization. Patients receive plerixafor SC 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 IV or prednisone PO on days -1 to 7 and undergo reinfusion of genetically modified hematopoietic stem/progenitor cells on day 0.

Procedure: Bone Marrow Aspiration
Undergo bone marrow harvest
Biological: Filgrastim
Given SC
Other Names:
  • Filgrastim XM02
  • Filgrastim-sndz
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tbo-filgrastim
  • Tevagrastim
  • Zarxio
Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells
Undergo infusion of genetically modified hematopoietic progenitor cell therapy
Other Name: Genetically Engineered HSPCs
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Methylprednisolone
Given IV
Other Names:
  • 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
Drug: Plerixafor
Given SC
Other Names:
  • AMD 3100
  • JM-3100
  • Mozobil
  • SDZ SID 791
Drug: Prednisone
Given PO
Other Names:
  • .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
Procedure: Leukapheresis
Undergo leukapheresis
Other Names:
  • Leukocytopheresis
  • Therapeutic Leukopheresis

Detailed Description:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. To determine the feasibility and efficacy of filgrastim (G-CSF) and plerixafor mobilization in FA patients.

II. To determine the feasibility and efficacy of lineage depletion of bone marrow or mobilized apheresis product.

III. 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.

IV. To determine if gene transfer using the clinical grade vector will result in phenotypic correction of gene modified cells by in vitro assays.

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

OUTLINE:

STEM CELL MOBILIZATION FOR CELL COLLECTION: Patients receive filgrastim subcutaneously (SC) twice daily (BID) for 5-6 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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   4 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, 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% 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01331018


Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Pamela S. Becker    206-288-7234    pbecker@u.washington.edu   
Principal Investigator: Pamela S. Becker         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Rocket Pharma Limited
Investigators
Principal Investigator: Pamela Becker Fred Hutch/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01331018     History of Changes
Other Study ID Numbers: 2097.00
NCI-2011-00202 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2097.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Submitted: March 16, 2011
First Posted: April 7, 2011
Last Update Posted: May 24, 2017
Last Verified: May 2017

Additional relevant MeSH terms:
Fanconi Anemia
Fanconi Syndrome
Anemia
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metabolism, Inborn Errors
Prednisolone acetate
Methylprednisolone acetate
Cortisone acetate
Prednisone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Cortisone
Prednisolone hemisuccinate
Prednisolone phosphate
Lenograstim
JM 3100
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists