Clinical Trial: Gene Therapy for Fanconi Anemia

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Gene Transfer for Patients With Fanconi Anemia Complementation Group A (FANCA)

Brief Summary: 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.

Detailed Summary:

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 bo
Sponsor: Fred Hutchinson Cancer Research Center

Current Primary Outcome:

  • 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.


Original Primary Outcome: Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Fifteen years ]

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.


Current Secondary Outcome:

  • 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.


Original Secondary Outcome:

  • Total Number of CD34+ Cells Mobilized per Kilogram Weight after G-CSF with Plerixafor (latter if age 18 or older) [ Time Frame: 5 days ]
    Total cell CD34+ cell count to be determined after completion of leukapheresis procedure.
  • Transduction efficiency [ Time Frame: 6th day ]
    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 ]
    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 ]
    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 ]
    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.


Information By: Fred Hutchinson Cancer Research Center

Dates:
Date Received: March 16, 2011
Date Started: February 22, 2012
Date Completion:
Last Updated: May 22, 2017
Last Verified: May 2017