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Gene Therapy for Wiskott-Aldrich Syndrome (TIGET-WAS)

Primary Purpose

Wiskott-Aldrich Syndrome (WAS)

Status

Active

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

OTL-103

About this trial

This is an interventional treatment trial for Wiskott-Aldrich Syndrome (WAS) focused on measuring Lentiviral vector, Gene therapy, Wiskott-Aldrich Syndrome, OTL-103, Previously GSK2696275

Eligibility Criteria

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

Inclusion Criteria:

Diagnosis of WAS defined by genetic mutation and at least one of the following criteria:
- Severe WAS mutation
- Absence of WASP expression
- Severe clinical score (Zhu clinical score ≥ 3
No HLA-identical sibling donor
Negative search for a matched unrelated donor (10/10) or an adequate unrelated cord blood donor (5-6/6) within 4-6 months
- Patients of > 5 years of age who are not candidate to unrelated allogeneic transplant based on clinical conditions.
Parental/guardian/patient signed informed consent.

Exclusion Criteria:

Patients positive for HIV-infection.
Patients affected by neoplasia.
Patients with cytogenetic alterations typical of MDS/AML.
Patients with end-organ functions or any other severe disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study.
Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months.
Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Sites / Locations

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

OTL-103 gene therapy

Arm Description

Eligible subjects will receive intravenous (IV) infusion of OTL-103 gene therapy. Subjects affected by WAS who don't have a suitable matched donor for allogenic hematopoietic stem cell transplantation will be included

Outcomes

Primary Outcome Measures

Conditioning regimen-related safety

Absence of engraftment failure or prolonged aplasia (<500/ul ANC with no evidence of bone marrow recovery) and surveillance of non haematological regimen related toxicity (for clinical features NCI >2, for metabolic/laboratory NCI >3)

Safety of lentivirus gene transfer into HSC

Short-term safety and tolerability of lentiviral-transduced cell infusion-long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferation).

Sustained engraftment of genetically corrected haematopoietic stem cells in peripheral blood and/or in bone marrow

≥ 0.04 Vector copy number (VCN)/cell in bone marrow CD34+ or ≥0.1 VCN/cell in peripheral blood T lymphocytes

Expression of vector-derived WASP

Detection of vector-derived WASP expression by FACS analyses and/or Western Blot

Improved T-cell functions

Improvement in in vitro T cell proliferation and/or IL-2 secretion upon stimulation with anti-CD3i as compared to pre-gene therapy values.

Antigen-specific responses to vaccination

Ability to mount a humoral response to nominal antigens including antibodies to T cell dependent antigens (Tetanus Toxoid) and unconjugated polysaccharide antigens (Peumococcus, Meningococcus), measured after vaccination (foreseen >1 year after gene therapy). Positive cellular response to Tetanus Toxoid after vaccination measured by in vitro proliferative response >1 year after gene therapy.

Improved platelet count and MPV normalization

Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile

Overall survival

Number of patients alive all over the trial

Secondary Outcome Measures

Lack of immune response to transgene

Immunoblot analysis

Reduced frequency of severe infections

Decrease in number of severe infections as evaluated in the second and third year after the treatment by clinical history, complete physical examinations, hematological and microbiological tests.

Reduced bruising and bleeding episodes

Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history

Reduced autoimmunity phenomena and eczema

Reduction in laboratory markers (number and titer of antibody when available) and/or clinical manifestations of autoimmunity, as evaluated by organ-specific and systemic autoantibodies, imaging and clinical follow-up, compared to clinical history. Reduction in eczema as evaluated by clinical score

Improved quality of life

Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.

Multilineage engraftment of genetically corrected cells

≥0.04 VCN/cell on all the available peripheral blood and/or bone marrow cell subpopulations (BM subpopulations: GlyA+, CD15+, CD61+, CD3+, CD19+, CD56+; PB subpopulations: CD15+, CD19+, CD56+)

Overall safety of the treatment

Recording of AE, AR, SAE/SAR, UAR, SUSAR

Full Information

NCT ID

NCT01515462

First Posted

December 23, 2011

Last Updated

February 2, 2023

Sponsor

Orchard Therapeutics

Collaborators

Ospedale San Raffaele

1. Study Identification

Unique Protocol Identification Number

NCT01515462

Brief Title

Gene Therapy for Wiskott-Aldrich Syndrome

Acronym

TIGET-WAS

Official Title

A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Wiskott-Aldrich Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

April 20, 2010 (Actual)

Primary Completion Date

October 3, 2018 (Actual)

Study Completion Date

September 11, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Orchard Therapeutics

Collaborators

Ospedale San Raffaele

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This is phase I/II protocol to evaluate the safety and efficacy of WAS gene transfer into hematopoietic stem/progenitor cells for the treatment of Wiskott Aldrich Syndrome.

Detailed Description

Wiskott-Aldrich Syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene which encodes the WAS protein (WASP), a cytoskeletal regulator which is expressed exclusively in hematopoietic cells.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Wiskott-Aldrich Syndrome (WAS)

Keywords

Lentiviral vector, Gene therapy, Wiskott-Aldrich Syndrome, OTL-103, Previously GSK2696275

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

This will be a single-arm study. All subjects will receive OTL-103 gene therapy and will be followed up for 15 years post gene therapy

Masking

None (Open Label)

Allocation

N/A

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

OTL-103 gene therapy

Arm Type

Experimental

Arm Description

Intervention Type

Genetic

Intervention Name(s)

OTL-103

Other Intervention Name(s)

Previously GSK2696275

Intervention Description

OTL-103 is an autologous CD34+ cells collected from bone marrow and/or peripheral blood and transduced with a lentiviral vector encoding Wiskott-Aldrich syndrome (WAS) protein

Primary Outcome Measure Information:

Title

Conditioning regimen-related safety

Description

Time Frame

Two months after gene therapy

Title

Safety of lentivirus gene transfer into HSC

Description

Time Frame

3 years

Title

Sustained engraftment of genetically corrected haematopoietic stem cells in peripheral blood and/or in bone marrow

Description

≥ 0.04 Vector copy number (VCN)/cell in bone marrow CD34+ or ≥0.1 VCN/cell in peripheral blood T lymphocytes

Time Frame

1 year

Title

Expression of vector-derived WASP

Description

Detection of vector-derived WASP expression by FACS analyses and/or Western Blot

Time Frame

1 year

Title

Improved T-cell functions

Description

Improvement in in vitro T cell proliferation and/or IL-2 secretion upon stimulation with anti-CD3i as compared to pre-gene therapy values.

Time Frame

3 years

Title

Antigen-specific responses to vaccination

Description

Time Frame

>1year

Title

Improved platelet count and MPV normalization

Description

Sustained increase in platelet count compared to baseline, analyzing the individual longitudinal profile

Time Frame

3 years

Title

Overall survival

Description

Number of patients alive all over the trial

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Lack of immune response to transgene

Description

Immunoblot analysis

Time Frame

3 years

Title

Reduced frequency of severe infections

Description

Decrease in number of severe infections as evaluated in the second and third year after the treatment by clinical history, complete physical examinations, hematological and microbiological tests.

Time Frame

3 years

Title

Reduced bruising and bleeding episodes

Description

Reduction in bruising and/or bleeding manifestations when present, as assessed by clinical monitoring, compared to clinical history

Time Frame

3 years

Title

Reduced autoimmunity phenomena and eczema

Description

Time Frame

3 years

Title

Improved quality of life

Description

Improved quality of life, measured after the first year of treatment by reduced hospitalization, reduced requirement of drugs, school attendance, social activities.

Time Frame

3 year

Title

Multilineage engraftment of genetically corrected cells

Description

≥0.04 VCN/cell on all the available peripheral blood and/or bone marrow cell subpopulations (BM subpopulations: GlyA+, CD15+, CD61+, CD3+, CD19+, CD56+; PB subpopulations: CD15+, CD19+, CD56+)

Time Frame

3 years

Title

Overall safety of the treatment

Description

Recording of AE, AR, SAE/SAR, UAR, SUSAR

Time Frame

8 years

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of WAS defined by genetic mutation and at least one of the following criteria: Severe WAS mutation Absence of WASP expression Severe clinical score (Zhu clinical score ≥ 3 No HLA-identical sibling donor Negative search for a matched unrelated donor (10/10) or an adequate unrelated cord blood donor (5-6/6) within 4-6 months Patients of > 5 years of age who are not candidate to unrelated allogeneic transplant based on clinical conditions. Parental/guardian/patient signed informed consent. Exclusion Criteria: Patients positive for HIV-infection. Patients affected by neoplasia. Patients with cytogenetic alterations typical of MDS/AML. Patients with end-organ functions or any other severe disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study. Patients who underwent an allogeneic haematopoietic stem cell transplantation in the previous 6 months. Patients who underwent an allogeneic haematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Orchard Clinical Trials

Organizational Affiliation

Orchard Therapeutics

Official's Role

Study Director

Facility Information:

Facility Name

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

City

Milan

ZIP/Postal Code

20132

Country

Italy

12. IPD Sharing Statement

Citations:

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Citation

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Gene Therapy for Wiskott-Aldrich Syndrome

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