Clinical trial NCT02906202: A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Participants With Transfusion-Dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype
Official title: A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects With Transfusion-dependent β-Thalassemia, Who do Not Have a β0/β0 Genotype, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Beta-Thalassemia
Lead sponsor: bluebird bio
Sponsor class: INDUSTRY
First posted: 2016-09-20
Enrollment: 24
Sex: ALL
Minimum age (years): 0
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-arm, multi-site, single-dose, Phase 3 study in 23 participants less than or equal to (\<=) 50 years of age with transfusion-dependent β-thalassemia (TDT), also known as β-thalassemia major, who do not have a β0 mutation at both alleles of the hemoglobin β (HBB) gene. The study will evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product.


Eligibility criteria: Inclusion Criteria:

* Participants \<= 50 years of age at the time of consent or assent (as applicable), and able to provide written consent (adults, or legal guardians, as applicable) or assent (adolescents or children). Provided that the Data Monitoring Committee (DMC) has approved enrolling participants younger than 5 years of age, participants younger than 5 years of age may be enrolled if they weigh a minimum of 6 kilograms (kg) and are reasonably anticipated to be able to provide at least the minimum number of cells required to initiate the manufacturing process.
* Diagnosis of TDT with a history of at least 100 milliliter per kilogram per year (mL/kg/year) of pRBCs in the 2 years preceding enrollment (all participants), or be managed under standard thalassemia guidelines with \>= 8 transfusions of pRBCs per year in the 2 years preceding enrollment (participants \>= 12 years).
* Clinically stable and eligible to undergo (HSCT).
* Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

Exclusion Criteria:

* Presence of a mutation characterized as β0 mutation at both alleles of the β-globin gene HBB.
* Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV).
* A white blood cell (WBC) count less than (\<) 3×10\^9/Liter (L), and/or platelet count \< 100×10\^9/L not related to hypersplenism.
* Uncorrected bleeding disorder.
* Any prior or current malignancy.
* Immediate family member with a known Familial Cancer Syndrome.
* Prior HSCT.
* Advanced liver disease.
* A cardiac T2\* \< 10 ms by MRI.
* Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion.
* Participation in another clinical study with an investigational drug within 30 days of Screening.
* Any other condition that would render the participant ineligible for HSCT, as determined by the attending transplant physician or investigator.
* Prior receipt of gene therapy.
* Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participant.
* A known and available Human leukocyte antigen (HLA) matched family donor.
* Any contraindications to the use of granulocyte colony stimulating factor (G-CSF) and plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.

Primary outcomes:
measure: Percentage of Participants Who Meet the Definition of Transfusion Independence (TI)
timeFrame: From 14 to 24 months post-transplant
Secondary outcomes:
measure: Percentage of Participants Who Meet the Definition of Transfusion Independence (TI) at Month 24
timeFrame: At Month 24 post-transplant
measure: Duration of Transfusion Independence (TI)
timeFrame: From start of TI up to Month 24
measure: Time From Drug Product Infusion to Achievement of Transfusion Independence (TI)
timeFrame: From 14 months post-drug product infusion through Month 24
measure: Weighted Average Hemoglobin (Hb) During Transfusion Independence (TI)
timeFrame: From 60 days after the last pRBC transfusion through Month 24
measure: Percentage of Participants Who Had a Reduction of At Least 50%, 60%, 75%, 90% or 100% in the Annualized pRBCs Transfusion Volume
timeFrame: 12 months post-drug product infusion through Month 24
measure: Annualized Number of pRBC Transfusions
timeFrame: From 12 months post-drug product infusion through Month 24
measure: Annualized Volume of pRBC Transfusions
timeFrame: From 12 months post-drug product infusion through Month 24
measure: Time From Drug Product Infusion to Last pRBC Transfusion
timeFrame: From start of drug product infusion up to Month 24
measure: Time From Last pRBC Transfusion to Month 24
timeFrame: From last pRBC Transfusion up to Month 24 (actual maximum time frame of up to approximately 27 months due to visit window)
measure: Weighted Average Nadir Hemoglobin (Hb)
timeFrame: 12 months post-drug product infusion through Month 24
measure: Unsupported Total Hb Levels at Month 6, 9, 12, 18 and 24
timeFrame: At Month 6, 9, 12, 18 and 24
measure: Number of Participants With Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) at Months 6, 9, 12, 18 and 24
timeFrame: At Month 6, 9, 12, 18 and 24
measure: Percentage of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion
timeFrame: Up to Month 24
measure: Time From Last Iron Chelation Use to Last Follow-up
timeFrame: Time from last iron chelation up to Month 24 (actual maximum time frame of up to approximately 27 months due to visit window)
measure: Percentage of Participants Who Used Therapeutic Phlebotomy Post Drug Product (DP) Infusion
timeFrame: Up to Month 24
measure: Annualized Phlebotomy Therapy Usage Following Drug Product Infusion
timeFrame: Up to Month 24
measure: Change From Baseline in Liver Iron Concentration by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in Cardiac T2* on MRI
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in Serum Ferritin at Months 12 and 24
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Total Scores at Months 12 and 24
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in EuroQol Quality of Life 5-Dimension Youth Scale (EQ-5D-Y) VAS Health Status at Months 12 and 24
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in EuroQol Quality of Life 5-Dimension Adult Scale (EQ-5D-3L) VAS Heath Status Score at Months 12 and 24
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2, Acute (Physical and Mental Component Summary Scores) at Months 12 and 24
timeFrame: Baseline, Months 12 and 24
Other outcomes:
Locations:
city: Oakland
country: United States
state: California
city: Chicago
country: United States
state: Illinois
city: Philadelphia
country: United States
state: Pennsylvania
city: Marseille
country: France
city: Hannover
country: Germany
city: Rome
country: Italy
city: Bangkok
country: Thailand
city: London
country: United Kingdom
Study officials:
affiliation: bluebird bio
name: Himal Lal Thakar, MD
role: STUDY_DIRECTOR
References:
citation: Locatelli F, Thompson AA, Kwiatkowski JL, Porter JB, Thrasher AJ, Hongeng S, Sauer MG, Thuret I, Lal A, Algeri M, Schneiderman J, Olson TS, Carpenter B, Amrolia PJ, Anurathapan U, Schambach A, Chabannon C, Schmidt M, Labik I, Elliot H, Guo R, Asmal M, Colvin RA, Walters MC. Betibeglogene Autotemcel Gene Therapy for Non-beta0/beta0 Genotype beta-Thalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11.
citation: Hamed EM, Meabed MH, Aly UF, Hussein RRS. Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia. Curr Drug Targets. 2019;20(16):1603-1623. doi: 10.2174/1389450120666190726155733.