A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in β-Thalassemia Major Participants

Study Overview
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Brief Summary
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This is a non-randomized, open label, multi-site, single-dose, phase 1/2 study in up to 18 participants (including at least 3 adolescents between 12 and 17 years of age, inclusive) with β-thalassemia major. The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product [autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene].

Detailed Description
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Subject participation for this study will be 2 years. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 13 years post-transplant.

Official Title
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A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With β-Thalassemia Major by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)

Conditions
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β-thalassemia Major

Intervention / Treatment
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* Genetic: LentiGlobin BB305 Drug Product


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants between 12 and 35 years of age, inclusive, at the time of consent/assent, and able to provide written consent/assent, if applicable. Diagnosis of β-thalassemia major and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years. Eligible for allogeneic bone marrow transplant. Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history. Exclusion criteria: Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2). A white blood cell (WBC) count <3 × 10^9/L, and / or platelet count <100 × 10^9/L if not due to hypersplenism. Uncorrected bleeding disorder. Any prior or current malignancy or myeloproliferative or immunodeficiency disorder. Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome and familial adenomatous polyposis). Receipt of an allogeneic transplant. Advanced liver disease, including persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 × the upper limit of normal, liver biopsy demonstrating cirrhosis, extensive bridging fibrosis, or active hepatitis. Kidney disease with a calculated creatinine clearance <30% normal value. Uncontrolled seizure disorder. Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin). A cardiac T2* <10 ms by magnetic resonance imaging (MRI). Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion. Clinically significant pulmonary hypertension, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen. Participation in another clinical study with an investigational drug within 30 days of Screening. Any prior or current malignancy or myeloproliferative disorder. Prior receipt of gene therapy.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LentiGlobin BB305 Drug Product<br> | Genetic: LentiGlobin BB305 Drug Product<br>* Transplant of autologous hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing βA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24 | Percentage of participants with sustained production of >=2.0 grams per deciliter (g/dL) of hemoglobin A (HbA) containing βA-T87Q-globin (HbAT87Q) for 6 months (Month 18 to Month 24) was reported. | Month 18 to Month 24 | 
| Percentage of Participants Who Achieved Transfusion Independence (TI) | TI was defined as a weighted average hemoglobin (Hb) >= 9 g/dL without any packed red blood cells (pRBC) transfusions for a continuous period of >=12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Percentage of participants who achieved TI from time of drug product infusion up to 24 months was reported. | From time of drug product infusion up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24 | TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. | Month 18, Month 24 | 
| Duration of Transfusion Independence (TI) | TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Time period of TI will start when participants achieve a Hb >= 9 g/dL with no transfusions in the preceding 60 days. Duration of TI was calculated as the time from the start of TI (i.e. first Hb >= 9 g/dL with no transfusions in the preceding 60 days) up to the last available Hb at which the TI criteria are still met. | From time of drug product infusion up to 24 months | 
| Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI) | TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Time From LentiGlobin BB305 Drug Product Infusion to last pRBC transfusion prior to achieving TI was reported. | From time of drug product infusion up to 24 months | 
| Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI) | TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Time from drug product infusion to initial achievement of TI was calculated as the time from drug product infusion to the first Hb at which a participant can be declared as TI. | From time of drug product infusion up to 24 months | 
| Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI) | The weighted average Hb is an average area under the curve during the period of TI, from the start of TI when the Hb is first >= 9 g/dL with no transfusions in the preceding 60 days to the last available Hb at which the TI criteria are still met. TI was defined as a weighted average Hb >= 9 g/dL without any pRBC transfusions for a continuous period of >= 12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Weighted average Hb during the period of TI was reported. | From time of drug product infusion up to 24 months | 
| Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24 | The annualized number of pRBC transfusions over the 2 year period prior to drug product infusion was compared to the annualized number of pRBC transfusions during the Month 6 to Month 24 period post drug product infusion and the percentage change was reported. | Baseline, Month 24 | 
| Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24 | The annualized volume of pRBC transfusions over the 2 year period prior to drug product infusion was compared to the annualized volume of pRBC transfusions in the Month 6 to Month 24 period post drug product Infusion and the percentage change from baseline was reported. | Baseline, Month 24 | 
| Weighted Average Nadir Hemoglobin (Hb) | Weighted average Hb nadir was defined as an average area under the curve where the Hb closest but within 3 days prior to a transfusion is used as the Hb nadir. If there is a period of more than 60 days without a pRBC transfusion, all Hb records between Day 61 and day of last visit or next transfusion (inclusive) were also considered as nadirs. The weighted average nadir Hb during the period of Month 6 to Month 24 was compared to the weighted average nadir Hb during the 2 years prior to enrollment. | Baseline, Month 6 to Month 24 | 
| Number of Participants With Successful Neutrophil Engraftment | Neutrophil engraftment was defined as achieving 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L on different days after a post-transplant value of < 0.5 × 10^9/L within 42 days after drug product infusion. | From time of drug product infusion up to 24 months | 
| Time to Neutrophil Engraftment | Time to neutrophil engraftment was defined as the time to the first of 3 consecutive absolute neutrophil count (ANC) >= 0.5 × 10^9/L obtained on different days after a post-transplant value of < 0.5 × 10^9/L. The Day of neutrophil engraftment is the first day of the 3 consecutive measurements, where Day 1 is the day of drug product infusion. | From time of drug product infusion up to 24 months | 
| Number of Participants With Successful Platelet Engraftment | Platelet engraftment was defined as achieving 3 consecutive platelet values >= 20 × 10^9/L on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. | From time of drug product infusion up to 24 months | 
| Time to Platelet Engraftment | Time to platelet engraftment was defined as achieving of first 3 consecutive platelet values >= 20 × 10^9/L obtained on different days after a post-transplant value of < 20 × 10^9/L, while no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of platelet engraftment is the first day of the 3 consecutive measurements, where Day 1 is the day of drug product infusion. | From time of drug product infusion up to 24 months | 
| Transplant-related Mortality | Transplant-related mortality was determined by the investigator (any deaths considered related to the transplant.) | Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion | 
| Overall Survival | Overall survival was defined as time from date of LentiGlobin BB305 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive. Percentage of participants who survived throughout the study were reported. | From time of drug product infusion up to 24 months | 
| Percentage of Participants Detected With Replication-competent Lentivirus (RCL) | Blood samples were analyzed for detection of RCL using RCL co-culture assay. | From time of drug product infusion up to 24 months | 
| Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution | Linear amplification-mediated polymerase chain reaction (LAM-PCR) coupled with next generation sequencing and subsequent (semi-) automated data mining allowed high-throughput analysis of vector integration site (IS) in blood cells from treated participants at multiple time points. ISs detected in peripheral blood cells at early time points generally were due to the expansion of transduced short-term progenitor stem cell clones, and gradually shift to include sites detected due to expansion of transduced long-term stem cell clones. An efficient transduction procedure was anticipated to give rise to a polyclonal population in the participant, reflected by the detection of multiple IS. Additionally, ISA allowed monitoring of the relative contribution of individual clones over time. Number of participants who had IS that contributed to >=30% of the total clones at any time was used as a first step to investigating whether clonal dominance was achieved. | From time of drug product infusion up to 24 months | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE, occurring at any dose and regardless of causality that: results in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect. | From signing of informed consent to 24 months after the drug product infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, β thalassemia, hemoglobin, anemia, CD34