A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT04293185
• Recruitment Status: Recruiting
• First Posted: March 3, 2020
• Last Update Posted: December 24, 2020
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Study Description

Brief Summary:

This is a non-randomized, open-label, multi-site, single-dose, Phase 3 study in approximately 35 adults and pediatric subjects ≥2 and ≤50 years of age with sickle cell disease (SCD). The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) with LentiGlobin BB305 Drug Product for SCD.

Condition or disease	Intervention/treatment	Phase
Sickle Cell Disease	Genetic: LentiGlobin BB305 Drug Product for SCD	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Sickle Cell Disease
• Actual Study Start Date: February 14, 2020
• Estimated Primary Completion Date: November 2023
• Estimated Study Completion Date: November 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: LentiGlobin BB305 Drug Product for SCD; Subjects will receive treatment with a single dose of Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis, transduced with BB305 lentiviral vector (LVV) encoding the human beta-A-T87Q globin gene. Plerixafor mobilization and apheresis will also be used for collection of rescue cells.

Genetic: LentiGlobin BB305 Drug Product for SCD; Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.

Outcome Measures

Primary Outcome Measures :

1. Proportion of subjects meeting Globin Response criteria [ Time Frame: 1-24 months post-transplant ]

   Subjects must meet the below criteria for a continuous period of at least 6 months after drug product infusion in order to be considered having achieved Globin response:

   1. Weighted average HbAT87Q percentage of total Hb* ≥30% AND

   2. Weighted average total Hb* increase of ≥3 g/dL compared to baseline total Hb* OR weighted average total Hb* ≥10 g/dL

      • total Hb is the non-transfused total Hb; it is HbS + HbF + HbA2 + HbAT87Q

Secondary Outcome Measures :

1. Percent of subjects reaching a 75% reduction in annualized severe vaso-occlusive events (sVOE-75) in the 24 months after drug product administration compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
2. Weighted average non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
3. Weighted average HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
4. Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
5. Weighted average HbAT87Q percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
6. Weighted average non-HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
7. Average and median of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
8. Average and median of HbS percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
9. Average and median of HbAT87Q percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
10. Average and median of non-HbS percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
11. Change from baseline in absolute reticulocyte count [ Time Frame: 1-24 months post-transplant ]
12. Change from baseline in percent reticulocytes [ Time Frame: 1-24 months post-transplant ]
13. Change from baseline in percent erythrocytes [ Time Frame: 1-24 months post-transplant ]
14. Change from baseline in total bilirubin [ Time Frame: 1-24 months post-transplant ]
15. Change from baseline in haptoglobin [ Time Frame: 1-24 months post-transplant ]
16. Change from baseline in lactate dehydrogenase [ Time Frame: 1-24 months post-transplant ]
17. Change from baseline in iron [ Time Frame: 1-24 months post-transplant ]
18. Change from baseline in ferritin [ Time Frame: 1-24 months post-transplant ]
19. Change from baseline in transferrin saturation [ Time Frame: 1 - 24 months post-transplant ]
20. Change from baseline in liver iron content [ Time Frame: 1-24 months post-transplant ]
21. Change from baseline in cardiac iron content (if assessed at baseline) [ Time Frame: 1-24 months post-transplant ]
22. Change from baseline in erythropoietin [ Time Frame: 1-24 months post-transplant ]
23. Change from baseline in serum transferrin receptor [ Time Frame: 1 - 24 months post-transplant ]
24. Change in the annualized number of severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
25. Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent [ Time Frame: 1-24 months post-transplant ]
26. Proportion of subjects achieving severe VOE-complete resolution (sVOE-CR) [ Time Frame: 6-24 months post-transplant ]
    Defined as complete resolution of severe VOEs between 6 months and 24 months after drug product administration
27. Proportion of subjects achieving reduction in the annualized number of severe VOEs of at least 90% in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
28. Change from baseline in annualized frequency transfusions [ Time Frame: 6-24 months post-transplant ]
29. Change from baseline in volume of packed red blood cell (pRBC) transfusions [ Time Frame: 6-24 months post-transplant ]
30. Change from baseline in cerebral vasculature and prior brain parenchymal injury [ Time Frame: Months 12 and 24 post-transplant ]
    As measured by cerebral MRA/MRI in all subjects, and transcranial doppler (TCD) for subjects ≤16 years old at Informed Consent
31. Change from baseline in bone mineral density (BMD) evaluation using dual x-ray (DXA) absorptiometry [ Time Frame: 24 months post-transplant ]
32. Proportion of subjects with the development of osteonecrosis in new joints needing any specific therapeutic procedure [ Time Frame: 1 - 24 months post-transplant ]
33. Proportion of subjects with new or worsening retinopathy complications needing any specific therapeutic procedure [ Time Frame: Months 12 and 24 post-transplant ]
34. Proportion of subjects with new or worsening severe leg ulcers needing wound care specialized follow-up [ Time Frame: Months 12 and 24 post-transplant ]
35. Change from baseline in proteinuria [ Time Frame: 1 - 24 months post-transplant ]
36. Change from baseline in microalbuminuria [ Time Frame: 1 - 24 months post-transplant ]
37. Change from baseline in estimated glomerular filtration rate (eGFR) [ Time Frame: 1 - 24 months post-transplant ]
38. Change from baseline in cardiac-pulmonary function via echocardiogram tricuspid regurgitant jet velocity (EKG TRJV) [ Time Frame: 1 - 24 months post-transplant ]
39. Change from baseline in cardiac-pulmonary function via pulmonary function test [ Time Frame: 1 - 24 months post-transplant ]
40. Change from baseline in cardiac-pulmonary function via brain natriuretic peptide [NT-proBNP] [ Time Frame: 1 - 24 months post-transplant ]
41. Change from baseline in meters walked during 6-minute walk test [ Time Frame: 1 - 24 months post-transplant ]
42. Change from baseline in annualized number of hospital admissions [ Time Frame: 1 - 24 months post-transplant ]
43. Change from baseline in annualized number of total days hospitalized [ Time Frame: 1 - 24 months post-transplant ]
44. Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System-57 (PROMIS-57) [ Time Frame: 1 - 24 months post-transplant ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Have a diagnosis of SCD, with either βS/βS, βS/β0 or βS/β+ genotype.
• Be ≥2 and ≤50 years of age at time of consent.
• Weigh a minimum of 6 kg.
• Have a Karnofsky performance status of ≥60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age).
• Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history.
• Have severe manifestations of SCD. i.e. in the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 severe VOEs in the 24 months prior to informed consent as defined below. For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a ≥24 -hour hospital or emergency room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion.
• Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment).

Exclusion Criteria:

• Applicable to subjects <18 years of age only: Availability of a willing, matched human leukocyte antigen (HLA)-identical sibling HSC donor.
• Severe cerebral vasculopathy, defined by any history of: overt ischemic or hemorrhagic stroke, abnormal transcranial Doppler (>200 cm/sec based on central read) requiring chronic transfusion, occlusion or stenosis in the circle of Willis, or presence of Moyamoya disease.
• Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotrophic virus-1 (HTLV-1) or -2 (HTLV-2), active syphilis.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection

• Advanced liver disease, such as

  1. clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy)
  2. liver iron concentration ≥15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis
• Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L.
• Any contraindications to the use of 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.
• Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment
• Unable to receive red blood cell (RBC) transfusion.
• Prior receipt of an allogeneic HSC transplant.
• Prior receipt of gene therapy.
• Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• Immediate family member with a known or suspected Familial Cancer Syndrome.
• Pregnancy, or breastfeeding in a postpartum female, or absence of adequate contraception for fertile subjects.
• Any other condition that would render the subject ineligible for HSCT.
• Participation in another clinical study with an investigational drug within 30 days of screening.

Contacts and Locations

Contacts

Contact: bluebird bio; +1-339-499-9300; clinicaltrials@bluebirdbio.com

Locations

United States, Alabama

University of Alabama; Active, not recruiting

Birmingham, Alabama, United States, 35233

United States, Massachusetts

Tufts Medical Center; Recruiting

Boston, Massachusetts, United States, 02111

United States, Minnesota

University of Minnesota; Recruiting

Minneapolis, Minnesota, United States, 55455

United States, New Jersey

Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

United States, North Carolina

Duke University; Recruiting

Durham, North Carolina, United States, 27705

United States, Texas

Baylor College of Medicine/Texas Children's Hospital; Recruiting

Houston, Texas, United States, 77030

Sponsors and Collaborators

bluebird bio

Investigators

• Study Director: Sunita Goyal, MD; bluebird bio, Inc.

More Information

• Responsible Party: bluebird bio
• ClinicalTrials.gov Identifier: NCT04293185
• Other Study ID Numbers: HGB-210
• First Posted: March 3, 2020
• Last Update Posted: December 24, 2020
• Last Verified: December 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn