Gene-Modified Stem Cell Therapy for Subjects With Transfusion-dependent Beta-thalassemia

A Single Arm, Open Label, Multicenter, Single-dose, Phase 2b Clinical Study Evaluating Efficacy and Safety of Gene Therapy Using Autologous CD34+ Hematopoietic Stem Cells Transduced With the GLOBE Lentiviral Vector Using an Improved Transduction Protocol in Subjects With Transfusion-dependent Beta-thalassemia

This is a prospective, dual-centre, single dose, Phase IIb, single arm, open label study. The proposed clinical trial involves a single infusion of autologous HSPCs genetically modified with the GLOBE lentiviral vector, using an improved transduction protocol in 9 patients affected by transfusion dependent Beta-Thalassemia.

Four study phases are foreseen:

1. Screening phase, during which the conditions required by the clinical protocol for patients' inclusion/exclusion will be assessed after the signature of the informed consents/assents. Patients will be recruited from the two participating sites: IRCCS Ospedale San Raffaele (OSR), Department of Pediatric Immunohematology and adult Hematology (OSR Stem Cells Programme) (Milan) and IRCCS Ospedale Pediatrico Bambino Gesù (OPBG), Department of Haematology, Oncology and Gene and Cell Therapy (Rome).
2. Baseline phase, carried from the end of the screening phase to the day before the start of the conditioning regimen.
3. Treatment phase, from the first day of conditioning regimen until DP administration.
4. Follow-up phase: from DP administration until 2 years follow-up.

Study Overview

• Status: Not yet recruiting
• Conditions: Transfusion-dependent Beta-Thalassemia
• Intervention / Treatment: Genetic: FT007

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pier Francesca Porceddu; Phone Number: +3902202217205; Email: pporceddu@telethon.it
• Study Contact Backup: Name: Elena Tomasetto; Phone Number: +3902202217222; Email: etomasetto@fondazionetelethon.it

Study Locations

• Italy
  • Lazio
    • Rome, Lazio, Italy, 00165
      • Ospedale Pediatrico Bambino Gesù
      • Contact: Franco Locatelli; Phone Number: +39 0668593697; Email: franco.locatelli@opbg.net
  • Lombardy
    • Milan, Lombardy, Italy, 20132
      • Ospedale San Raffaele
      • Contact: Alessandro Aiuti; Phone Number: +39 02 26439057; Email: aiuti.alessandro@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Must be willing to adhere to the protocol as evidenced by written informed consent for adults or parental informed consent and subject assent for adolescents and children.
2. Male and female adults/adolescents/children diagnosed with transfusion-dependent β-thalassemia (homozygous or compound heterozygous). At least 2 out of the 9 patients must have B0/B0 or B0/B0-like genotype. In case the genetic diagnosis available at screening wasn't performed in a certified laboratory (check under PI's or delegated investigator's responsibility), the genetic diagnosis will be repeated at clinical sites during the screening phase.
3. Documented history of at least 100 ml/kg/year or 10 U/year of packed red blood cell transfusions in each of the 2 years prior to signing informed consent.
4. Age ≥ 18 years and ≤ 35 years for Group 1, Age ≥ 3 years and ≤ 35 years for Group 2.
5. Karnofsky Index or Lansky ≥ 80%.

6. Adequate cardiac, renal, hepatic and pulmonary functions resulting in eligibility to undergo autologous HSCT as evidenced by:

   1. Left ventricular ejection fraction (LVEF) greater than 45% by echo and normal ECG or presence of abnormalities not significant for cardiac disease. Absence of severe pulmonary hypertension.
   2. Diffusing capacity of the lung for carbon monoxide (DLCO) > 50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) > 60% predicted (if non cooperative: pulse oximetry > 95 % in room air).
   3. Serum creatinine < 2 x upper limit of normal and estimated GFR > 60 ml/min/1.73m2, calculated using the CKD-EPI formula (Levey 2009) for adults and the modified Schwartz formula (Schwartz 2009) for pediatric patients.
   4. Absent-mild-moderate liver iron overload on T2*MRI (i.e. LIC < 15 mg Fe/gr dry weight assessed at screening. T2*MRI at screening can be avoided if performed less than 6 months before enrolment at treatment centers).
   5. Absent-mild-moderate cardiac iron overload T2*MRI (i.e. > 20 msec assessed at screening. T2*MRI at screening can be avoided if performed less than 6 months before enrolment at treatment centers).
   6. Absence of severe liver fibrosis or cirrhosis on Shear Wave (less than 6 months before enrolment) or of other advanced liver disorder.
7. For all patients in reproductive age, agreement to use highly effective and adequate method of contraception for at least 12 months following DP administration (including both females of childbearing potential and males with partners of childbearing potential).
8. Good adherence to transfusion and chelation programme, as indirect evidence of good adherence to treatment and follow-up evaluations for the current trial.
9. Availability of an adequate and well documented transfusion history (at least previous 24 months) or availability to follow a regular transfusion regimen according to guidelines and provide a detailed transfusion record of the 24 months prior to the DP administration.

Exclusion Criteria:

1. Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents).
2. Severe, active viral, bacterial or fungal infection at eligibility evaluation.
3. Current or prior malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes.
4. Current or prior immunodeficiency disorder.
5. History of uncontrolled seizures.
6. Aspartate transaminase (AST), alanine transaminase (ALT) >3 × the upper limit of normal (ULN), or direct bilirubin value >2.5 × ULN.
7. Baseline prothrombin time (International Normalized Ratio; INR) >1.5 × ULN.
8. Other clinical conditions judged non compatible with the procedure and/or the treatment.
9. Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (patients who have completed antiviral treatment for HCV may only be enrolled if they have achieved a sustained virologic response, defined as undetectable HCV RNA at least 12 weeks after completion of therapy) and/or evidence of active infection of Treponema Pallidum or Mycoplasma species.
10. Positive history of significant previous thrombotic events. In case of a positive thrombophilic screening, patient's inclusion will be evaluated according to national guidelines.
11. Active alcohol or substance abuse within 6 months of the study.
12. Pregnancy or lactation.
13. Previous allogeneic hematopoietic stem cell transplantation.
14. Previous gene therapy treatment (gene addition or gene editing).
15. For patients until the age of 14 years only: availability of an HLA-matched family donor.
16. Patients with associated α-thalassemia and >1 alpha deletion, or alpha multiplications.
17. Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study and, in the opinion of the investigator, makes the potential subject unsuitable for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: subjects with transfusion-dependent beta-thalassemia	Genetic: FT007; Autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with the lentiviral vector GLOBE encoding for the human beta globin using an improved transduction protocol, re-suspended in their final formulation medium and cryopreserved.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects who achieve TI12 in the 2 years from DP administration	Proportion of Subjects achieving transfusion independence defined as a weighted average Hb ≥ 9.0 gr/dL without any red blood cell transfusion for a continuous period of ≥ 12 months (TI12) at any time during the study after the drug product administration The assessment of TI12 starts 60 days after last RBC transfusion for post-transplant support or BTHAL standard of care.	from 60 days after the IMP infusion, to 24 months of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival at 12 and 24 months post IMP infusion	12 months and 24 months post IMP infusion
Proportion of Subjects who achieve hematological engraftment ≤ day +60 from DP administration	Proportion of Subjects who achieve hematological engraftment ≤ day +60 from DP administration defined as first day of absolute neutrophil count ≥ 0.5 x 10^9/L on 3 consecutive measurements obtained on different days and platelets ≥20x 10^9/L in the absence of platelet transfusions and/or growth factor support for at least 7 consecutive days.	from Day 11 to Day 60 post IMP infusion
Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) (Safety and tolerability of the administration of FT007)	Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) attributed to procedures related to harvesting of HSPCs, conditioning regimen, FT007 administration (from screening to 24 months post GT).	from Baseline to 24 months post IMP infusion
Proportion of Subjects with abnormal clonal proliferation development due to insertional mutagenesis	Proportion of Subjects with abnormal clonal proliferation development due to insertional mutagenesis	6, 12, 18 and 24 months post IMP infusion
Polyclonal and multilineage engraftment evaluated by VCN and ISA	ISA will be carried out at 3, 6, 12, 18, 24 months on total nucleated cells and different hematopoietic lineages (granulocytes, lymphocytes, erythroid cells) from PB and/or BM. The criteria to assess "polyclonality" of hematopoiesis is defined as > 1000 unique integration sites retrieved at 3, 6, 12, 18 and 24 months after gene therapy from PB and/or BM cells when available. Clonal dominance will be assessed from 3 months after GT and will be defined as the presence of a vector integration that constitutes > 30% with respect to the total integrations retrieved from whole peripheral blood cells in at least 3 consecutive timepoints and with an increase in the relative contribution over time. Vector-specific quantitative PCR will be performed on PB and/or BM erythroid cells at screening, 1, 2, 3, 6, 12,18 and 24 months after GT (at 1 and 18 months only on PB, at 24 months after GT. Adequate engraftment is defined as ≥ 0.8 VCN/genome on BM erythroid cells and CD15+ cells.	screening, 1, 2, 3, 6, 12, 18 and 24 months after IMP infusion
Proportion of Subjects with immune reconstitution	Proportion of Subjects with immune reconstitution defined as CD4+ >200 at 6 and 12 months post GT. Immune-monitoring will be evaluated at baseline and at follow-up time points (6 and 12 months of follow-up). The frequency and functionality of lymphoid compartment (B, T, NK cells) in PB and BM, including humoral and cellular responses will be evaluated.	6 and 12 months post IMP infusion
Characterization of Subjects achieving TI12	Duration of TI12 and the time from IMP infusion to last RBC transfusion prior to becoming TI12 will be evaluated. Weighted average Hb during TI12 and the proportion of subjects who meet the definition of TI12 at 24 months will be also evaluated.	24 months after IMP infusion
Characterization of transfusion reduction (TR) among subjects not achieving TI12	Percentage of treated subjects with a reduction in the ml/kg RBC transfused from Month 12 through Month 24 (a 12-month period) after DP infusion of at least 50%, 60%, 75%, 90% or 100% compared to the average annual ml/kg RBC transfusion requirement during the 2 years prior to enrolment will be recorded. Moreover, the number of transfusions from Month 12 through Month 24 compared to the average number of annual transfusions during the 2 years prior to enrolment will be collected and analyzed. Two years of retrospective pre-transplant data will be collected for each subject in the study, so that each subject may serve as his/her own control for the parameters of RBC transfusion requirements.	12 and 24 months post IMP infusion
Health-related quality of life (HRQoL) - PedsQL	HRQoL will be assessed by the use of standardized questionnaires: PedsQL quality of life version 4.0 up to 25 years of age, according to patient's age. PedsQL quality of life will be assessed at 12 and 24 months of follow-up compared to baseline.	baseline, 12 and 24 months
Health-related quality of life (HRQoL) - FACT BMT	HRQoL will be assessed by the use of standardized questionnaires: FACT BMT version 4 for adults. FACT BMT will be assessed at 12 and 24 months of follow-up compared to baseline.	baseline, 12 and 24 months
Health-related quality of life (HRQoL) - EQ-5D-5L	HRQoL will be assessed by the use of standardized questionnaires: EuroQol Quality of Life Scale-5 dimensions-5 levels of severity (EQ-5D-5L) for adults	baseline, 12 and 24 months
Health-related quality of life (HRQoL) - EQ-5D-Y	HRQoL will be assessed by the use of standardized questionnaires: EuroQol Quality of Life Scale-5 dimensions-5 levels of severity the EuroQol Quality of Life Scale-5 dimensions youth (EQ-5D-Y) for children and adolescents.	baseline, 12 and 24 months
Proportion of Subjects with engraftment of genetically corrected cells	Proportion of Subjects with engraftment of genetically corrected cells (expressed as VCN ≥ 0.8 on bone marrow erythroid cells and CD15+ cells). Engraftment will be assessed by vector-specific quantitative PCR on bone marrow erythroid cells at 6, 12, and 24 months after IMP infusion.	6, 12, and 24 months after IMP infusion
Levels of biomarkers indicative of ineffective erythropoiesis before and after gene therapy at different time points.	Evaluation of plasma iron level, erythropoietin (EPO), soluble serum transferrin receptor (sTfR), Lactate Dehydrogenase (LDH) and Bilirubin will be evaluated as surrogate of ineffective erythropoiesis at screening and 1, 3, 6, 12, 24 months. Decreased levels of these parameters correlate with ineffective erythropoiesis improvement.	screening and 1, 3, 6, 12, 24 months after IMP infusion
Shear Wave Elastography and Liver Iron Concentration (LIC) over time	Shear Wave Elastography and LIC will be performed at screening and at 12, 24 months after infusion of DP (T2*MRI at screening can be avoided if performed less than 6 months before enrolment at treatment sites); in selected cases liver biopsy can be performed.	screening, 12 and 24 months after IMP infusion
Cardiac T2* value over time	Cardiac T2* value will be assessed through T2*MRI at screening and at 12, 24 months after infusion of DP (T2*MRI at screening can be avoided if performed less than 6 months before enrolment at treatment sites).	screening, 12 and 24 months after IMP infusion
Ferritin serum levels over time	Serum ferritin will be evaluated at screening, 3, 6, 12, 18, 24 months after infusion of DP.	screening, 3, 6, 12, 18 and 24 months after IMP infusion
Proportion of patients free from any iron-chelating therapy, including regular phlebotomies at month 24	The proportion of patients free from iron-chelation therapy, including regular phlebotomies in the entire cohort will be evaluated at month 24 after infusion of DP.	24 months after IMP infusion
Duration of iron-chelating treatment after DP infusion	The duration of iron chelation therapy following DP infusion will be assessed. This includes the time from DP infusion to the last documented administration of iron chelation treatment.	from Day 1 to 24 months post IMP infusion

Collaborators and Investigators

• Sponsor: Fondazione Telethon
• Collaborators: Ospedale San Raffaele
• Investigators: Study Director: Elena Tomasetto, Fondazione Telethon ETS

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2030

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: July 1, 2026
• First Posted (Actual): July 2, 2026

Study Record Updates

• Last Update Posted (Actual): July 2, 2026
• Last Update Submitted That Met QC Criteria: July 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: BTHAL-FT007-01; 2025-522160-32-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No