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Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant (TigetT10_MPSIH)

Primary Purpose

Mucopolysaccharidosis IH

Status

Active

Phase

Phase 1

Locations

Italy

Study Type

Interventional

Intervention

Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.

About this trial

This is an interventional treatment trial for Mucopolysaccharidosis IH focused on measuring Mucopolysaccharidosis IH, Gene Therapy, Transplantation, Autologous, Lentiviral vector

Eligibility Criteria

28 Days - 11 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent by parent/legal guardian
Sex: Males and Females
Age: ≥ 28 days and ≤ 11 years old
Biochemically and molecularly proven MPS IH
Lansky index >80%
Indication to hematopoietic stem cell transplant
Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10^7 Total Nucleated Cells (TNC)/Kg after 1-month search.(This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantion).
Adequate cardiac, renal, hepatic and pulmonary functions

Exclusion Criteria:

Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
Severe, active viral, bacterial or fungal infection at eligibility evaluation
Patients affected by neoplasia or family history of familial cancer syndromes
Cytogenetic alterations associated with high risk of developing hematological malignancies
History of uncontrolled seizures
Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection
Patients with DQ/IQ <70
Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product
Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)

Sites / Locations

Ospedale San Raffaele

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Gene therapy (autologous, CD34+ cell enriched cells fraction containing HSCs, transduced with the IDUA LV encoding for the human IDUA gene and cryopreserved in cryoformulation medium)

Outcomes

Primary Outcome Measures

Overall survival

Number of subjects alive at the end of the trial

Achievement of haematological engraftment

First day of neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 on 3 consecutive days (in the absence of transfusions).

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability

Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus

Percentage of subjects without Replication Competent Lentivirus

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation

Percentage of subjects without abnormal clonal proliferation

Overall safety and tolerability (AE)

The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated.

IDUA activity in blood

IDUA activity measured on peripheral blood dried spot

Secondary Outcome Measures

Anti-IDUA antibody immune response

Presence and titer of anti-IDUA antibody on serum

Achievement of supraphysiologic IDUA activity in blood

IDUA activity measured on peripheral blood dried spot up to supraphysiologic levels as compared with healthy donors. A supraphysiologic IDUA level is defined as >24.31 μmol/L/h, which is the 97.5 percentile of the IDUA distribution in healthy children.

IDUA activity in plasma

IDUA activity measured on plasma samples from peripheral blood.

Engraftment of transduced cells at levels above 30%

Engraftment will be assessed by vector-specific quantitative PCR on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM). Adequate engraftment is defined as ≥ 0.30 VCN/genome

Normalization of urinary GAGs

Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC

Normalization of spleen and liver

Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound

Growth velocity

length/height for age and cm/year percentiles

Full Information

NCT ID

NCT03488394

First Posted

March 22, 2018

Last Updated

August 6, 2021

Sponsor

IRCCS San Raffaele

Collaborators

Fondazione Telethon

1. Study Identification

Unique Protocol Identification Number

NCT03488394

Brief Title

Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant

Acronym

TigetT10_MPSIH

Official Title

Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem and Progenitor Cells Genetically Modified With IDUA Lentiviral Vector Encoding for the Human α-L-iduronidase Gene for the Treatment of Patients Affected by Mucopolysaccharidosis Type I, Hurler Variant

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Active, not recruiting

Study Start Date

May 11, 2018 (Actual)

Primary Completion Date

January 2025 (Anticipated)

Study Completion Date

January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

IRCCS San Raffaele

Collaborators

Fondazione Telethon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant

Detailed Description

Pediatric patients with mucopolysaccharidosis type I will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow if mobilization is not feasible) and transduced with IDUA lentiviral vector encoding for the human α-L-iduronidase gene. Patients will be followed for 5 years after gene therapy. After completing participation in this study, subjects will be offered enrollment into an approved long term follow-up (LTFU) study which will enable continued follow-up for up to 15 years post-treatment (per regulatory guidelines for follow up of patients treated with ATMPs).

6. Conditions and Keywords

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

Mucopolysaccharidosis IH

Keywords

Mucopolysaccharidosis IH, Gene Therapy, Transplantation, Autologous, Lentiviral vector

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

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Gene therapy (autologous, CD34+ cell enriched cells fraction containing HSCs, transduced with the IDUA LV encoding for the human IDUA gene and cryopreserved in cryoformulation medium)

Intervention Type

Genetic

Intervention Name(s)

Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.

Intervention Description

The drug product target dose is more or equal to 8x10^6 CD34+ cells/Kg, with a minimum dose of 4x10^6 CD34+ cells/Kg and a maximum dose of 35x10^6 CD34+ cells/Kg. The product will be injected intravenously.

Primary Outcome Measure Information:

Title

Overall survival

Description

Number of subjects alive at the end of the trial

Time Frame

5 year

Title

Achievement of haematological engraftment

Description

First day of neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 on 3 consecutive days (in the absence of transfusions).

Time Frame

within day +45 after gene therapy

Title

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability

Description

Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions

Time Frame

0-24 hours from injection

Title

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus

Description

Percentage of subjects without Replication Competent Lentivirus

Time Frame

0-5 years after gene therapy

Title

Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation

Description

Percentage of subjects without abnormal clonal proliferation

Time Frame

0-5 years after gene therapy

Title

Overall safety and tolerability (AE)

Description

Time Frame

0-5 years after gene therapy

Title

IDUA activity in blood

Description

IDUA activity measured on peripheral blood dried spot

Time Frame

1, 3 and 5 years post treatment

Secondary Outcome Measure Information:

Title

Anti-IDUA antibody immune response

Description

Presence and titer of anti-IDUA antibody on serum

Time Frame

0-5 years after gene therapy

Title

Achievement of supraphysiologic IDUA activity in blood

Description

Time Frame

1, 3 and 5 years after gene therapy

Title

IDUA activity in plasma

Description

IDUA activity measured on plasma samples from peripheral blood.

Time Frame

1, 3 and 5 years after gene therapy

Title

Engraftment of transduced cells at levels above 30%

Description

Engraftment will be assessed by vector-specific quantitative PCR on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM). Adequate engraftment is defined as ≥ 0.30 VCN/genome

Time Frame

by year 1 and after 3 and 5 years from gene therapy

Title

Normalization of urinary GAGs

Description

Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC

Time Frame

1, 3 and 5 years after gene therapy

Title

Normalization of spleen and liver

Description

Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound

Time Frame

1, 3 and 5 years after gene therapy

Title

Growth velocity

Description

length/height for age and cm/year percentiles

Time Frame

1, 3 and 5 years after gene therapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

28 Days

Maximum Age & Unit of Time

11 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Written informed consent by parent/legal guardian Sex: Males and Females Age: ≥ 28 days and ≤ 11 years old Biochemically and molecularly proven MPS IH Lansky index >80% Indication to hematopoietic stem cell transplant Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10^7 Total Nucleated Cells (TNC)/Kg after 1-month search.(This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantion). Adequate cardiac, renal, hepatic and pulmonary functions Exclusion Criteria: Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents) Severe, active viral, bacterial or fungal infection at eligibility evaluation Patients affected by neoplasia or family history of familial cancer syndromes Cytogenetic alterations associated with high risk of developing hematological malignancies History of uncontrolled seizures Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection Patients with DQ/IQ <70 Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)

Facility Information:

Facility Name

Ospedale San Raffaele

City

Milano

ZIP/Postal Code

20132

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant

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