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

• ClinicalTrials.gov Identifier: NCT02906202
• Recruitment Status: Completed
• First Posted: September 20, 2016
• Last Update Posted: April 27, 2022
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Study Description

Brief Summary:

This is a single-arm, multi-site, single-dose, Phase 3 study in approximately 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.

Condition or disease	Intervention/treatment	Phase
Beta-Thalassemia	Genetic: LentiGlobin BB305 Drug Product	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: July 2016
• Actual Primary Completion Date: March 31, 2022
• Actual Study Completion Date: March 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: LentiGlobin BB305 Drug Product; LentiGlobin BB305 Drug Product (autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene)	Genetic: LentiGlobin BB305 Drug Product; LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.; Other Name: betibeglogene autotemcel

Outcome Measures

Primary Outcome Measures :

1. The Proportion of Participants who Meet the Definition of Transfusion Independence (TI) [ Time Frame: From 12 to 24 months post-transplant ]
   TI is defined as a weighted average Hb greater than or equal to (>=) 9 grams per deciliter (g/dL) without any packed red blood cell (pRBC) transfusions for a continuous period of >= 12 months at any time during the study after drug product infusion.

Secondary Outcome Measures :

1. Proportion of Participants who Meet the Definition of Transfusion Independence (TI) at Month 24 [ Time Frame: At Month 24 post-transplant ]
2. Duration of Transfusion Independence (TI) [ Time Frame: Up to 24 months post-transplant ]
3. Time From Drug Product Infusion to Achievement of Transfusion Independence (TI) [ Time Frame: Up to 24 months post-transplant ]
4. Average Weighted Hemoglobin (Hb) During Transfusion Independence (TI) [ Time Frame: From 12 to 24 months post-transplant ]
5. Proportion of Participants with At least 50%, 60%, 75%, 90% or 100% Reduction in the Annualized pRBCs Transfusion [ Time Frame: From 12 to 24 months post-transplant ]
   Reduction in the annualized mL/kg pRBCs transfused from 12 months post-drug product infusion through Month 24 (approximately a 12-month period) of at least 50%, 60%, 75%, 90% or 100% compared to the annualized mL/kg pRBC transfusion requirement during the 24 months prior to enrollment.
6. Annualized Number of pRBC Transfusions [ Time Frame: From 12 to 24 months post-transplant ]
   Annualized number of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized number of transfusions during the 24 months prior to enrollment.
7. Annualized Volume of pRBC Transfusions [ Time Frame: From 12 to 24 months post-transplant ]
   Annualized volume of pRBC transfusions from 12 months post-drug product infusion through Month 24 compared to the annualized volume of transfusions during the 24 months prior to enrollment.
8. Time From Drug Product Infusion to Last pRBC Transfusion [ Time Frame: Up to 24 months post-transplant ]
9. Time From Last pRBC Transfusion to the Month 24 [ Time Frame: Up to 24 months post-transplant ]
10. Weighted Average Nadir Hemoglobin (Hb) [ Time Frame: From 12 to 24 months post-transplant ]
    Weighted average nadir Hb during the 24 months prior to enrollment compared to weighted average nadir Hb from 12 months post-drug product infusion through the Month 24 Visit.
11. Unsupported Total Hb Levels Over Time [ Time Frame: At Month 6, 9, 12, 18 and 24 ]
12. Unsupported Total Hb Levels (>=10 g/dL, >=11 g/dL, >=12 g/dL, >=13 g/dL, and >=14 g/dL) [ Time Frame: At Month 6, 9, 12, 18 and 24 ]
13. Proportion of Participants Who Have Not Received Chelation Therapy for At Least 6 Months Following Drug Product Infusion [ Time Frame: From 6 to 24 months ]
14. Time from Last Iron Chelation Use to Last Follow-up [ Time Frame: Up to 24 months ]
15. Proportion of Participants Using Therapeutic Phlebotomy and Annualized Frequency of Phlebotomy [ Time Frame: Up to 24 months ]
16. Change From Baseline in liver Iron Content by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline, Month 12 and 24 ]
17. Change From Baseline in Cardiac T2 on MRI [ Time Frame: Baseline, Month 12 and 24 ]
18. Change From Baseline in Serum Ferritin [ Time Frame: Baseline, Month 12 and 24 ]
19. Change From Baseline in Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale (GCS) Score [ Time Frame: Baseline, Month 12 and 24 ]
    PedsQL GCS is designed to measure health-related quality of life in pediatric participants and adolescents (2 to 18 years of age). It encompasses 4 dimensions of functioning (physical [8 items], emotional [5 items], social [5 items], school [3 items]). Age groups: Toddler (2-4 years), Young pediatric (5-7 years), Pediatric (8-12 years), and Teens (13-18 years). Depending on the participant's age, the questionnaire may be completed by parent/caregiver as appropriate. For the Toddler group, the PedsQL GCS consist of 21 items, using a 5-point Likert scale (0 to 4); for all other groups, the PedsQL GCS consist of 23 items, with a 3-point Likert scale (0, 2, 4) for the young pediatric, and a 5-point Likert scale for the pediatric and teens groups. Scores are transformed on a scale from 0 to 100 where 0=100, 1=75, 2=50, 3=25, and 4=0. Higher scores indicate improved quality of life.
20. Change From Baseline in EuroQol-5D (Youth version) (EQ-5D-Y) [ Time Frame: Baseline, Month 12 and 24 ]
    EQ-5D-Y health questionnaire is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.
21. Change From Baseline in EuroQol-5D (EQ-5D) [ Time Frame: Baseline, Month 12 and 24 ]
    The EQ-5D provides a descriptive profile and index value for health status. The questionnaire measures 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response: no problems, slight problems, moderate problems, severe problems, and unable to do/extreme problems.
22. Change From Baseline in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Questionnaire Score [ Time Frame: Baseline, Month 12 and 24 ]
    The FACT-BMT assesses bone marrow transplant related concerns. The total score is the sum of sub-scale scores for 5 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Bone Marrow Transplantation Subscale. Within each domain, a 5-point Likert-type scale (from 0-4) is used to measure the responses for each question. After taking into account reverse scores for questions constructed in a negative form, the subscale score for each domain is calculated by multiplying the sum of the item scores by the number of items in the subscale, then dividing by the number of items answered. The final score for FACT-BMT ranges from 0 to 148. Higher scores indicate better quality of life.
23. Change From Baseline in Short Form-36 Health Survey (SF-36), Version 2 [ Time Frame: Baseline, Month 12 and 24 ]
    SF-36 is a generic quality-of-life instrument that had been widely used to assess HRQL of participants. Generic instruments were used in general populations to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. The SF-36 consisted of 36 items that were aggregated into 8 multi-item scales (physical functioning [1=yes, limited a lot to 3=no, not limited at all], role-physical [1=all of the time to 5=none of the time], bodily pain [1=very severe to 6=none], general health [1=poor to 5=excellent], vitality [1=none of the time to 5=all of the time], social functioning [1=all of the time: to 5=none of the time], role emotional [1=all of the time to 5=none of the time] and mental health [1=all of the time to 5=none of the time]), with scores ranged from 0 to 100. Higher scores indicating better HRQL.

Eligibility Criteria

• Ages Eligible for Study: 0 Years to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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) gene.
• 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.

Contacts and Locations

Locations

United States, California

Oakland, California, United States

United States, Illinois

Chicago, Illinois, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

France

Marseille, France

Germany

Hannover, Germany

Italy

Rome, Italy

Thailand

Bangkok, Thailand

United Kingdom

London, United Kingdom

Sponsors and Collaborators

bluebird bio

Investigators

• Study Director: Richard Colvin; bluebird bio

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: bluebird bio
• ClinicalTrials.gov Identifier: NCT02906202
• Other Study ID Numbers: HGB-207
• First Posted: September 20, 2016
• Last Update Posted: April 27, 2022
• Last Verified: April 2022

Additional relevant MeSH terms:

Thalassemia; beta-Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn