A phase I/II open label study to assess safety, feasibility and efficacy of ex vivo expanded, autologous haematopoietic stem and progenitor cell populations that contain CD34+ cells transduced with a lentiviral vector encoding the TCIRG1 cDNA in children with autosomal recessive osteopetrosis caused by mutations in the TCIRG1 gene.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Telethon Ets, San Raffaele Hospital

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Decision date (initial)

2025-08-06

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the safety and efficacy of autologous TCIRG1 LVV-transduced, ex vivo-expanded HSPC in paediatric patients with ARO-1

Secondary objectives 3

1. To evaluate the safety and tolerability of durably engrafting autologous TCIRG1 LVV-transduced, ex vivo-expanded HSPC in paediatric patients with ARO-1
2. To evaluate the feasibility of durably engrafting autologous TCIRG1 LVV-transduced, ex vivo-expanded HSPC in pediatric patients with ARO-1
3. To evaluate the efficacy of durably engrafting autologous TCIRG1 LVV-transduced, ex vivo-expanded HSPC in paediatric patients with ARO-1

Conditions and MedDRA coding

Autosomal recessive osteopetrosis caused by mutations in the TCIRG1 gene

Regulatory references

Scientific advice from competent authorities

Italian National Institute Of Health

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 1. Diagnosis of autosomal recessive osteopetrosis caused by mutations in the TCIRG1 gene, defined by one of the following: Clinical Trial Protocol Document FORM SOP-SC-008.02 Revision 2 Page 16 of 39 EU CT number: 2024-518972-30-00 Protocol number: ARO-FT024-01 Protocol date: 12/02/2025 Protocol version: 1.0 TEMP SOP-GEN-000.05 Rev.4 a. Clinical features of osteopetrosis and documented pathogenic/likely pathogenic biallelic variants (homozygosity or compound heterozygosity, whereby at least 1 allele must contain a known pathogenic mutation) in the TCIRG1 gene causing malignant infantile osteopetrosis. b. If a patient presents with clinical features suggestive of severe osteopetrosis (e.g., generalized osteosclerosis, club-shaped long bones, skull base sclerosis, recurrent fractures and osteomyelitis, cranial nerve entrapment leading to visual and/or hearing loss, bone marrow insufficiency) and at least one pathogenic/likely pathogenic mutation of the TCIRG1 gene.
2. 2. Age: ≥ 28 days and ≤ 2 years old
3. 3. Body weight: ≥ 4 kg

Exclusion criteria 1

1. 1. Availability of a medically appropriate, logistically feasible, fully HLA-matched (10/10) sibling or unrelated donor. The chances of finding a suitable, fully matched unrelated donor should be estimated through a preliminary donor bank search by an experienced transplant team. If the patient is judged unlikely to be treated with a fully matched allogeneic HSCT within 6 weeks from activating search procedures, he/she can be considered eligible for this gene therapy study. This criterion will not be applied to patients whose country of origin does not offer an allogeneic HSCT as a treatment option.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. a. Overall survival following the first ATMP infusion.
2. b. Percentage of patients who experience absence of neutropenia or thrombocytopenia > grade 3 and no regular need of red blood cell (RBC) transfusions as compared to baseline in the patients with long-term engraftment of TCIRG1 LVV-transduced cells, as defined by vector copy number (VCN) > 0.2 in total blood or myeloid cells at 12 months post first ATMP infusion, in the absence of rescue treatments (allogeneic transplantation +/- autologous back-up infusion).

Secondary endpoints 7

1. Secondary Endpoints of Safety a. Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) attributed to procedures related to the harvesting of HSPCs, to conditioning or to ATMP (0-24 months from the first ATMP administration). b. Absence of malignancy or abnormal clonal proliferation evaluated at 6, 12 and 24 months post first ATMP infusion. c. Absence of Replication Competent Lentivirus at 1, 6, 12 and 24 months post first ATMP infusion.
2. Secondary Endpoints of Feasibility a. Percentage of patients for whom at least the minimum number of autologous HSPCs (≥10x106 CD34+ cells/kg, as specified in the protocol) can be collected for manufacturing. b. Percentage of patients for whom a FT024 product conforming to specifications was manufactured and released.
3. Secondary Endpoints of Efficacy: a. Disability-free survival at baseline and at 24 months post first ATMP infusion, defined as absence of ≥ grade 3 neutropenia/thrombocytopenia, no requirement for chronic transfusion of blood products, no osteomyelitis, no requirement for major neurosurgery, and no pathologic bone fractures during the previous 12 months. b. Time to achieve hematologic recovery§ from the first ATMP infusion.
4. Secondary Endpoints of Efficacy: c. Percentage of patients who do not require a rescue treatment (autologous back-up infusion and/or allogeneic transplant). d. Change in neutrophil counts and platelets levels at 1, 2, 3, 6, 9, 12, 18 and 24 months post first ATMP infusion from baseline. e. Change in monthly RBC and platelets transfusion requirement at 1, 2, 3, 6, 12, 18 and 24 months post first ATMP infusion from baseline.
5. Secondary Endpoints of Efficacy: f. Impact of boost infusion on hematological recovery (neutrophils and platelets levels, RBC and platelets transfusions). g. Engraftment of TCIRG1 LVV-transduced cells, as assessed by longitudinal analysis of vector copy number (VCN) in leukocyte populations from blood and/or bone marrow at 1, 2, 3, 6, 9, 12, 18 and 24 months post first ATMP infusion.
6. Secondary Endpoints of Efficacy: h. Percentage of patients who experience long-term engraftment of TCIRG1 LVV-transduced cells, as defined by vector copy number (VCN) >0.2 in total blood or myeloid cells at 12 months post first ATMP infusion, in the absence of neutropenia or thrombocytopenia > grade 3 and no regular need of RBC transfusions as compared to baseline, in the absence of rescue treatments (allogeneic transplantation +/- autologous back-up infusion), stratified by number of boost.
7. Secondary Endpoints of Efficacy: i. Quality of life (PedsQL 4.0 generic core - Parent-proxy report for Toddler (2-4 years), PedsQL Infant Scales, Stem-cell transplant module), parents reported outcome measures at baseline and at 12 and 24 months after the first ATMP infusion.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Telethon Ets

Sponsor organisation

Fondazione Telethon Ets

Address

Via Varese 16 B

City

Rome

Postcode

00185

Country

Italy

Scientific contact point

Organisation

Fondazione Telethon Ets

Contact name

Regulatory Affairs

Public contact point

Organisation

Fondazione Telethon Ets

Contact name

Clinical development and operations

Third parties 8

San Raffaele Hospital

Sponsor organisation

San Raffaele Hospital

Address

Via Olgettina 58

City

Milan

Postcode

20132

Country

Italy

Sponsor responsibilities

Article 77 compliance

Fondazione Telethon Ets

Contact point sponsor

Fondazione Telethon Ets

Article 77 implementation

Fondazione Telethon Ets

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications