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Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA in Artemis (DCLRE1C) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE) (ARTEGENE)

Primary Purpose

Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency

Status
Not yet recruiting
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
ARTEGENE drug product
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency focused on measuring Artemis deficient Severe Combined Immunodeficiency, Severe Combined Immunodeficiency, Gene therapy, Allogeneic hematopoietic stem cells transplantation

Eligibility Criteria

undefined - 1 Year (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient less than one year
  • SCID patients with confirmed biallelic mutations in the Artemis (DCLRE1C) gene
  • Absence of an HLA genoidentical donor or without rapidly available HLA-compatible unrelated donor (within six weeks of diagnosis)
  • The patient can be treated by gene therapy without delay in case of active life threatening infections compromising the short-term prognosis and for which the delay in finding a phenoidentical donor is incompatible with the patient's condition of health. Active life threatening infections are defined as: viral respiratory infection, CMV infection, adenovirus infection, disseminated BCGitis or other infections grade ≥ 4 according to CTCAE scale
  • Parental, guardian's patient signed informed consent.

Exclusion Criteria

  • Unwillingness to return for follow-up during the first 2 years study and the long term follow-up
  • HIV-1 or 2 or HTLV1 infections
  • Hypersensitivity to nivestim or busulfan
  • Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.

Sites / Locations

  • Department of Pediatric Immunology, Hematology and Rheumatology UIHR, Necker-Enfants Malades Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ARTEGENE drug product

Arm Description

Autologous purified CD34+ cells transduced with a self-inactivated lentiviral vector, expressing the DCLRE1C gene (alias Artemis)

Outcomes

Primary Outcome Measures

Incidence of transplant related mortality
Incidence of transplant related mortality
Transgene copy number on peripheral blood mononuclear cells (PBMCs)
by qPCR
Transgene copy number on sorted cell populations
Determined on sorted cell populations CD15+,CD14+, CD19+, CD56+ and CD3+ T lymphocytes by qPCR
Detection of replication-competent lentivirus (RCL)
Absence of any severe adverse events due to insertional mutagenesis
Change in Artemis mRNA levels
by RT-qPCR performed on the transduced CD34+ cells in the drug substance and on peripheral blood mononuclear cells (PBMC)
Adverse events
Frequency and severity of clinical AEs and changes in laboratory parameters
Transgene copy number in the transduced CD34+ cells in the drug substance
by qPCR
Change in total number of T cells
by flow cytometry
Change in distribution of different subpopulations
by flow cytometry, according to the WBC count: Naïve and activated/memory CD4+ and CD8+ T cells will be evaluated using CCR7/CD45RA/CD45RO markers. Early thymic emigrants will be monitored by detecting CD31+CD45RA+CD4+ T lymphocytes; Stem cell-like memory CD8+ and CD4+ T cells will be quantified by counting CCR7+CD45RA+CD8+ T cells. Evaluation of the distribution of TCRαβ and TCRγδ T cells
Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens
Change in repertoire of T lymphocytes
via high-throughput sequencing of the TCR
Evaluation of the B lymphocyte compartment
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Evaluation of the B lymphocyte compartment
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Evaluation of the B lymphocyte compartment
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)

Secondary Outcome Measures

End of ongoing infection before the transplantation
Kinetics of immune reconstitution
Kinetics of immune reconstitution
Adverse event
Adverse event will be measured using CTCAE

Full Information

First Posted
August 27, 2021
Last Updated
September 26, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT05071222
Brief Title
Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA in Artemis (DCLRE1C) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE)
Acronym
ARTEGENE
Official Title
A Phase 1/2 Open Label Non Randomized Study, Multicentric, Single Arm Evaluating the Safety and Efficacy of Gene Therapy of the Severe Combined Immunodeficiency (SCID) Caused by Mutations in the Human DCLRE1C Gene (Artemis) by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 2023 (Anticipated)
Primary Completion Date
January 2041 (Anticipated)
Study Completion Date
January 2041 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the Safety and Efficacy of Gene Therapy of the severe combined immunodeficiency (SCID) caused by mutations in the human DCLRE1C gene (Artemis) by transplantation of a single dose of autologous CD34+ cells transduced ex vivo with the G2ARTE lentiviral vector expressing the DCLRE1C cDNA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency
Keywords
Artemis deficient Severe Combined Immunodeficiency, Severe Combined Immunodeficiency, Gene therapy, Allogeneic hematopoietic stem cells transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ARTEGENE drug product
Arm Type
Experimental
Arm Description
Autologous purified CD34+ cells transduced with a self-inactivated lentiviral vector, expressing the DCLRE1C gene (alias Artemis)
Intervention Type
Genetic
Intervention Name(s)
ARTEGENE drug product
Intervention Description
Each patient will receive a single intravenous infusion of ARTEGENE drug product at D0.
Primary Outcome Measure Information:
Title
Incidence of transplant related mortality
Time Frame
Up to 100 days post treatment
Title
Incidence of transplant related mortality
Time Frame
At 6 months post treatment
Title
Transgene copy number on peripheral blood mononuclear cells (PBMCs)
Description
by qPCR
Time Frame
Up to 15 years post treatment
Title
Transgene copy number on sorted cell populations
Description
Determined on sorted cell populations CD15+,CD14+, CD19+, CD56+ and CD3+ T lymphocytes by qPCR
Time Frame
Up to 15 years post treatment
Title
Detection of replication-competent lentivirus (RCL)
Time Frame
3 months post treatment
Title
Absence of any severe adverse events due to insertional mutagenesis
Time Frame
Up to 15 years post treatment
Title
Change in Artemis mRNA levels
Description
by RT-qPCR performed on the transduced CD34+ cells in the drug substance and on peripheral blood mononuclear cells (PBMC)
Time Frame
At Day 0, 12 months and 24 months post treatment
Title
Adverse events
Description
Frequency and severity of clinical AEs and changes in laboratory parameters
Time Frame
Up to 15 years post treatment
Title
Transgene copy number in the transduced CD34+ cells in the drug substance
Description
by qPCR
Time Frame
At Day 0
Title
Change in total number of T cells
Description
by flow cytometry
Time Frame
6, 12, 24 months post treatment
Title
Change in distribution of different subpopulations
Description
by flow cytometry, according to the WBC count: Naïve and activated/memory CD4+ and CD8+ T cells will be evaluated using CCR7/CD45RA/CD45RO markers. Early thymic emigrants will be monitored by detecting CD31+CD45RA+CD4+ T lymphocytes; Stem cell-like memory CD8+ and CD4+ T cells will be quantified by counting CCR7+CD45RA+CD8+ T cells. Evaluation of the distribution of TCRαβ and TCRγδ T cells
Time Frame
6, 12, 24 months post treatment
Title
Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens
Time Frame
6, 12, 24 months post treatment
Title
Change in repertoire of T lymphocytes
Description
via high-throughput sequencing of the TCR
Time Frame
12, 24 months post treatment
Title
Evaluation of the B lymphocyte compartment
Description
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Time Frame
6 months post treatment
Title
Evaluation of the B lymphocyte compartment
Description
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Time Frame
At 12 months post treatment
Title
Evaluation of the B lymphocyte compartment
Description
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Time Frame
At 24 months post treatment
Secondary Outcome Measure Information:
Title
End of ongoing infection before the transplantation
Time Frame
Up to 15 years post treatment
Title
Kinetics of immune reconstitution
Description
Kinetics of immune reconstitution
Time Frame
Up to 15 years post treatment
Title
Adverse event
Description
Adverse event will be measured using CTCAE
Time Frame
Up to 15 years post treatment

10. Eligibility

Sex
All
Maximum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient less than one year SCID patients with confirmed biallelic mutations in the Artemis (DCLRE1C) gene Absence of an HLA genoidentical donor or without rapidly available HLA-compatible unrelated donor (within six weeks of diagnosis) The patient can be treated by gene therapy without delay in case of active life threatening infections compromising the short-term prognosis and for which the delay in finding a phenoidentical donor is incompatible with the patient's condition of health. Active life threatening infections are defined as: viral respiratory infection, CMV infection, adenovirus infection, disseminated BCGitis or other infections grade ≥ 4 according to CTCAE scale Parental, guardian's patient signed informed consent. Exclusion Criteria Unwillingness to return for follow-up during the first 2 years study and the long term follow-up HIV-1 or 2 or HTLV1 infections Hypersensitivity to nivestim or busulfan Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marina CAVAZZANA, MD, PhD
Phone
+33 144495068
Email
m.cavazzana@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Jinmi BAEK, Master
Phone
+33 1 42 19 28 49
Email
jinmi.baek@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessandra MAGNANI, MD, PhD
Organizational Affiliation
Department of Biotherapy,LTCG, Necker-Enfants Malades Hospital
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Chantal Lagresle-Peyrou, MD
Organizational Affiliation
IMAGINE
Official's Role
Study Director
Facility Information:
Facility Name
Department of Pediatric Immunology, Hematology and Rheumatology UIHR, Necker-Enfants Malades Hospital
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Despina MOSHOUS, MD, PhD
Email
despina.moshous@aphp.fr

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA in Artemis (DCLRE1C) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE)

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