Gene-Modified Stem Cell Therapy for Children With Autosomal Recessive Osteopetrosis (ARO)

Overview

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.

This phase I/IIa clinical trial is a non-randomized, open label, single-centre, therapeutic-exploratory, prospective study, to assess safety and efficacy of FT024 in up to 8 children affected by ARO aged ≤2 years of age and will be carried out at the Pediatric Clinical Research Unit/Pediatric Immuno-haematology and Bone Marrow Transplantation Unit, IRCCS Ospedale San Raffaele, Milan, Italy. Once written informed consent has been obtained and subsequently screening procedures have been completed, harvesting of HSPCs will occur. In cases of strong suspicion of osteopetrosis without a confirmed genetic diagnosis, and when the patient is unable to visit the clinical center for this inclusion criteria analysis due to their clinical condition, a preliminary remote evaluation for gene mutation analysis may be considered. In this case, remote signing of genetic analysis consent will be required before any evaluation and a blood sample will be sent to the laboratory in Milan, where the analysis will be performed. Blood sample will be collected at a local health care provider (HCP) or local healthcare facility or by home nursing. If the diagnosis of TCIRG1-associated ARO is confirmed, patients who initially underwent genetic analysis remotely may proceed to Ospedale San Raffaele to complete the screening assessments. In such case, before undergoing any further screening procedures, the patient or parent/legal guardian will be asked to sign the main informed consent for participation in the clinical study. After completing the screening assessments and confirming eligibility, harvesting of HSPCs by leukapheresis or serial blood withdrawal will occur after mobilization and then sent to GMP facility to ATMP manufacturing. Following ATMP release, patients will be admitted to hospital for receipt of a reduced toxicity conditioning regimen based on Treosulfan and Thiotepa, and infusion of the ATMP. In-patient monitoring will occur until haematological recovery occurred. Thereafter, regular follow-up of patients will take place until 2 years (+720 days). In case of logistical issues or patient's needs, remote visits can be performed. Within the first 180 days, the patient may be re-admitted to hospital for infusion of 1 or 2 ATMP boost doses if the criteria for incomplete hematologic recovery are fulfilled. At the end of the study (+720 days), patients will be invited to continue long-term follow-up (up to 15 years after gene therapy administration), as required by the authorities (Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products. January 2018, EMEA/149995/2008 rev.1, Committee for Medicinal Products for Human Use \[CHMP\]). Additional written informed consent will be obtained to participate in this long-term follow-up study. Recruitment of the planned 8 patients is expected to take around 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. A total of 10 visits (minimum) will be required including assessments, day hospital visits and in-patient hospitalization(s).