Gene-Modified Stem Cell Therapy for Children With Autosomal Recessive Osteopetrosis (ARO)
ConditionOsteopetrosis
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age28-2
SponsorFondazione Telethon
About this trial
This is a non-randomized, one-arm, open label, single-center, phase I/II, prospective study, to assess safety, feasibility and efficacy of FT024 in 8 children (Age: ≥ 28 days and ≤ 2 years old, Body weight: ≥ 4 kg) affected by ARO-1.
Once written informed consent has been obtained, and subsequently screening procedures have been completed, harvesting of HSPCs will occur. FT024 manufacturing will occur within a designated GMP manufacturing facility. Following FT024 release, patients will be admitted to the clinical center for the receipt of a reduced toxicity conditioning regimen based on Treosulfan and Thiotepa and then, the infusion of the FT024. Thereafter, regular follow-up of patients will occur for up to 2 years (+720 days).
In case of partial hematological recovery, additional FT024 boost will be administered without conditioning within + 180 days post first FT024 infusion. At the +720-day visit, patients will be invited to participate in a long-term follow-up study, which will last for an additional 13 years.
Patient recruitment is expected to take 3 years. The study will last approximately 5 years and 6 months, from the first visit of the first patient to the final visit of the last patient. Each patient will take part in the study for about 30 months, from screening to last follow up visit.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
If a patient presents with clinical features suggestive of severe osteopetrosis (i.e. 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, the patient is eligible following discussion with an expert in this pathology.
Patient's parents/legal guardians' capacity to understand the study goals, the study requirements (i.e., attending study visits, completing questionnaires, taking study medications), potential risks associated with joining a study, and willingness to provide verbal and written informed consent.
Age: ≥ 28 days and ≤ 2 years old.
Disqualifiers
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.
History of uncontrolled seizures or severe psychiatric symptoms.
Clinically relevant active viral, bacterial or fungal infection.
Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or active infection for Treponema Pallidum or Mycoplasma.
Trial design
Design model
Single group
Treatments tested in this trial
FT024
GeneticAutologous haematopoietic stem and progenitor cell population containing CD34+ cells transduced with a lentiviral vector encoding the TCIRG1 cDNA and expanded ex vivo.
Treatment groups
8 Participants
are divided into 1 treatment groupGroup A: Open Label study with ex vivo expanded FT024 drug productExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Overall Survival
Overall survival following the first FT024 infusion.
Time frame
12 months and 24 months2
Percentage of Participants Achieving Long-Term Engraftment Without Severe Cytopenias, Regular Red Blood Cell Transfusions, or Rescue Treatment.
Long-term engraftment of TCIRG1 LVV-Transduced Cells is defined as vector copy number (VCN) \>0.2 in total blood or myeloid cells at 12 months after the first FT024 infusion. The endpoint is the percentage of participants who have no neutropenia or thrombocytopenia greater than Grade 3 and no regular red blood cell transfusion requirement compared with baseline, in the absence of rescue treatment (allogeneic transplantation with or without autologous back-up infusion).
Time frame
12 monthsSecondary outcomes
1
Percentage of Participants for Whom the Minimum Number of Autologous HSPCs Can Be Collected for Manufacturing
Percentage of patients for whom at least the minimum number of autologous HSPC (\>10x106 CD34+ cells/kg) can be obtained. The cumulative amount of CD34+ cells that has been collected during one or several apheresis and/or blood withdrawal sessions, will be calculated and referred to the patient weight at the time of the last HSPC harvest.
Time frame
Baseline2
Frequency and Severity of Adverse Events and Serious Adverse Events
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) attributed to procedures related to hematopoietic stem cell harvesting, conditioning regimen, or ATMP administration.
Time frame
From Baseline up to Month 24.3
Incidence of Malignancy or Abnormal Clonal Proliferation
Absence of malignancy or abnormal clonal proliferation assessed at 6, 12, and 24 months after first ATMP infusion. Evaluation includes clinical assessment, hematology and biochemistry tests, flow cytometry for lymphocyte subpopulations, vector copy number analysis, and bone marrow examination when clinically indicated. Additional investigations, including cytogenetic and molecular analyses, may be performed in case of suspected clonal expansion.
Time frame
6, 12, and 24 months4
Disability-Free Survival
Disability-free survival defined as absence of Grade ≥3 neutropenia or thrombocytopenia, no requirement for chronic blood product transfusion, no osteomyelitis, no requirement for major neurosurgery, and no pathologic bone fractures during the preceding 12 months.
Time frame
Baseline and 24 monthsSponsors and contacts
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Fondazione Telethon
Lead sponsor
Ospedale San Raffaele
Collaborator
Source ClinicalTrials.gov