A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease

NCT02151526 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: HGB-2052012-000695-42
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to participants with either transfusion dependent beta-thalassemia (TDT) or sickle cell disease (SCD).

Conditions

Beta-Thalassemia Major; Sickle Cell Disease

Outcome Measures

Primary Outcomes (7)

• Number of Treated Participants With Successful Neutrophil and Platelet Engraftment

  Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) \> or = 0.5 × 10\^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (\<) 0.5 × 10\^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values \> or =20 × 10\^9/L for participants with TDT and values \> or =50 × 10\^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements.

  From time of drug product infusion through Month 24

• Time to Successful Neutrophil and Platelet Engraftment

  Neutrophil engraftment was defined as the first of ANC \> or = 0.5 × 10\^9/ liter (L) for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value \< 0.5 × 10\^9/L). Platelet engraftment was defined as the first of 3 consecutive platelet values \> or =20 × 10\^9/L for participants with TDT and values \> or =50 × 10\^9/L for participants with SCD obtained on different days with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. The day of engraftment is the first day of the 3 consecutive platelet measurements.

  From time of drug product infusion through Month 24

• Incidence of Transplant Related Mortality

  This was the safety outcome measure related to mortality. Transplant related mortality was defined as any death occurring in the study post drug product infusion deemed related to the transplant by the investigator.

  From screening through 365 days post-transplant

• Number of Participants With Overall Survival (OS) Events

  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. Number of participants with OS events were reported.

  From time of drug product infusion through Month 24

• Percentage of Participants With Vector-Derived Replication-Competent Lentivirus (RCL)

  Blood samples were analyzed for detection of RCL using RCL co-culture assay.

  From time of drug product infusion through Month 24

• Number of Treated Participants With Greater Than (>) 30 Percent (%) Contribution of an Individual Clone As Per Integration Site Analysis (ISA)

  Clonal dominance was defined as an ISA result greater than (\>) 90% of the total insertion sites (IS) at any time and a vector copy number (VCN) \> or =0.3, or an initial ISA result of \> 30% of the total IS with a VCN \> or =0.3 followed by a result \> 30% and less than or equal to (\< or =) 90% at first repeat and a result \> 50% at second repeat.

  From time of drug product infusion through Month 24

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study. This definition includes inter-current illnesses or injuries, and exacerbation of pre-existing conditions. An SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed previously. The number of participants with AEs and SAEs were evaluated.

  From date of Informed Consent signing up to Month 24

Secondary Outcomes (11)

• Percentage of Treated Participants With Transfusion-Dependent β-Thalassemia (TDT) Who Achieved Transfusion Independence (TI)

  From time of drug product infusion through Month 24

• Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT)

  From time of drug product infusion through Month 24

• Duration of Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT)

  From time of drug product infusion through Month 24

• Time From LentiGlobin BB305 Drug Product Infusion to Last Packed Red Blood Cells (pRBC) Transfusion Prior to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT)

  From time of drug product infusion through Month 24

• Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI) in Participants With Transfusion-Dependent β-Thalassemia (TDT)

  From time of drug product infusion through Month 24

Study Arms (1)

LentiGlobin BB305 Drug Product

EXPERIMENTAL

Following myeloablative conditioning with IV busulfan for 4 consecutive days (dose may be adjusted as per protocol) and subsequent daily monitoring of busulfan levels for confirmation of adequate washout, a single dose cluster of differentiation (CD) 34+ cells/kg LentiGlobin BB305 Drug Product was administered to participants by IV infusion.

Drug: LentiGlobin BB305 Drug Product

Interventions

LentiGlobin BB305 Drug Product DRUG

LentiGlobin BB305 Drug Product was administered by intravenous (IV) infusion.

LentiGlobin BB305 Drug Product

Eligibility Criteria

• Age: 5 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Be between 5 and 35 years of age, inclusive.
• Have severe SCD or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs).
• Be eligible for allogeneic hematopoietic stem cell transplant (HSCT) based on institutional medical guidelines, but without a matched related donor.
• Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol.
• Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.
• Participants with severe SCD also must:
• Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated.
• Have 1 or more of the following poor prognostic risk factors:
• Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
• Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
• Stroke without any severe cognitive disability.
• Osteonecrosis of 2 or more joints.
• Anti-erythrocyte alloimmunization (\>2 antibodies).
• Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
• Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever \[\>38.5°C\], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Participants with a chronic oxygen saturation \<90% (excluding periods of SCD crisis) or carbon monoxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.

You may not qualify if:

• Availability of a willing 10 /10 matched human leukocyte antigen (HLA) identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comite de Surveillance following a review of the case.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection.
• Contraindication to anesthesia for bone marrow harvesting.
• Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
• A white blood cell (WBC) count \<3×10\^9/L and/or platelet count \<120×10\^9/L.
• History of major organ damage including:
• Liver disease, with transaminase levels \>3× upper limit of normal.
• Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy.
• Heart disease, with a left ventricular ejection fraction \<25%.
• Kidney disease with a calculated creatinine clearance \<30% normal value.
• A cardiac T2\* \<10 ms by magnetic resonance imaging (MRI).
• Evidence of clinically significant pulmonary hypertension requiring medical intervention.

Sponsors & Collaborators

• Genetix Biotherapeutics Inc.: lead

Study Sites (1)

Unknown Facility

Paris, France

Location

Related Publications (3)

• Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, Gabrion A, Roudaut C, Marouene J, Lefrere F, Diana JS, Denis A, Neven B, Funck-Brentano I, Negre O, Renolleau S, Brousse V, Kiger L, Touzot F, Poirot C, Bourget P, El Nemer W, Blanche S, Treluyer JM, Asmal M, Walls C, Beuzard Y, Schmidt M, Hacein-Bey-Abina S, Asnafi V, Guichard I, Poiree M, Monpoux F, Touraine P, Brouzes C, de Montalembert M, Payen E, Six E, Ribeil JA, Miccio A, Bartolucci P, Leboulch P, Cavazzana M. Long-term outcomes of lentiviral gene therapy for the beta-hemoglobinopathies: the HGB-205 trial. Nat Med. 2022 Jan;28(1):81-88. doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.

  PMID: 35075288 DERIVED

• Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479-1493. doi: 10.1056/NEJMoa1705342.

  PMID: 29669226 DERIVED

• Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L, Neven B, Bourget P, El Nemer W, Bartolucci P, Weber L, Puy H, Meritet JF, Grevent D, Beuzard Y, Chretien S, Lefebvre T, Ross RW, Negre O, Veres G, Sandler L, Soni S, de Montalembert M, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 2017 Mar 2;376(9):848-855. doi: 10.1056/NEJMoa1609677.

  PMID: 28249145 DERIVED

MeSH Terms

Conditions

beta-Thalassemia; Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Thalassemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Study Medical Director
• Organization: bluebird bio, Inc.

medinfo@bluebirdbio.com

339-499-9300

Study Officials

• Jean-Antoine Ribeil, MD

  bluebird bio, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2014
• First Posted: May 30, 2014
• Study Start: June 7, 2013
• Primary Completion: February 26, 2019
• Study Completion: February 26, 2019
• Last Updated: April 26, 2022
• Results First Posted: March 10, 2020

Record last verified: 2022-04

Locations

FR (1)