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

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

Sponsors

Lead Sponsor: bluebird bio

Source bluebird bio
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.

Overall Status Recruiting
Start Date February 14, 2020
Completion Date November 2023
Primary Completion Date November 2023
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Proportion of subjects meeting Globin Response criteria 1-24 months post-transplant
Secondary Outcome
Measure Time Frame
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. 1-24 months post-transplant
Weighted average non-transfused total Hb Month 6, 12, 18 and 24 post-transplant
Weighted average HbS percentage of non-transfused total Hb Month 6, 12, 18 and 24 post-transplant
Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% Month 6, 12, 18 and 24 post-transplant
Weighted average HbAT87Q percentage of non-transfused total Hb Month 6, 12, 18 and 24 post-transplant
Weighted average non-HbS percentage of non-transfused total Hb Month 6, 12, 18 and 24 post-transplant
Average and median of non-transfused total Hb over time 1-24 months post-transplant
Average and median of HbS percentage of non-transfused total Hb over time 1-24 months post-transplant
Average and median of HbAT87Q percentage of non-transfused total Hb over time 1-24 months post-transplant
Average and median of non-HbS percentage of non-transfused total Hb over time 1-24 months post-transplant
Change from baseline in absolute reticulocyte count 1-24 months post-transplant
Change from baseline in percent reticulocytes 1-24 months post-transplant
Change from baseline in percent erythrocytes 1-24 months post-transplant
Change from baseline in total bilirubin 1-24 months post-transplant
Change from baseline in haptoglobin 1-24 months post-transplant
Change from baseline in lactate dehydrogenase 1-24 months post-transplant
Change from baseline in iron 1-24 months post-transplant
Change from baseline in ferritin 1-24 months post-transplant
Change from baseline in transferrin saturation 1 - 24 months post-transplant
Change from baseline in liver iron content 1-24 months post-transplant
Change from baseline in cardiac iron content (if assessed at baseline) 1-24 months post-transplant
Change from baseline in erythropoietin 1-24 months post-transplant
Change from baseline in serum transferrin receptor 1 - 24 months post-transplant
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. 1-24 months post-transplant
Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent 1-24 months post-transplant
Proportion of subjects achieving severe VOE-complete resolution (sVOE-CR) 6-24 months post-transplant
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. 1-24 months post-transplant
Change from baseline in annualized frequency transfusions 6-24 months post-transplant
Change from baseline in volume of packed red blood cell (pRBC) transfusions 6-24 months post-transplant
Change from baseline in cerebral vasculature and prior brain parenchymal injury Months 12 and 24 post-transplant
Change from baseline in bone mineral density (BMD) evaluation using dual x-ray (DXA) absorptiometry 24 months post-transplant
Proportion of subjects with the development of osteonecrosis in new joints needing any specific therapeutic procedure 1 - 24 months post-transplant
Proportion of subjects with new or worsening retinopathy complications needing any specific therapeutic procedure Months 12 and 24 post-transplant
Proportion of subjects with new or worsening severe leg ulcers needing wound care specialized follow-up Months 12 and 24 post-transplant
Change from baseline in proteinuria 1 - 24 months post-transplant
Change from baseline in microalbuminuria 1 - 24 months post-transplant
Change from baseline in estimated glomerular filtration rate (eGFR) 1 - 24 months post-transplant
Change from baseline in cardiac-pulmonary function via echocardiogram tricuspid regurgitant jet velocity (EKG TRJV) 1 - 24 months post-transplant
Change from baseline in cardiac-pulmonary function via pulmonary function test 1 - 24 months post-transplant
Change from baseline in cardiac-pulmonary function via brain natriuretic peptide [NT-proBNP] 1 - 24 months post-transplant
Change from baseline in meters walked during 6-minute walk test 1 - 24 months post-transplant
Change from baseline in annualized number of hospital admissions 1 - 24 months post-transplant
Change from baseline in annualized number of total days hospitalized 1 - 24 months post-transplant
Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System-57 (PROMIS-57) 1 - 24 months post-transplant
Enrollment 35
Condition
Intervention

Intervention Type: Genetic

Intervention Name: LentiGlobin BB305 Drug Product for SCD

Description: Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.

Arm Group Label: LentiGlobin BB305 Drug Product for SCD

Eligibility

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.

Gender: All

Minimum Age: 2 Years

Maximum Age: 50 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Sunita Goyal, MD Study Director bluebird bio, Inc.
Overall Contact

Last Name: bluebird bio

Phone: +1-339-499-9300

Email: [email protected]

Location
Facility: Status:
University of Alabama | Birmingham, Alabama, 35233, United States Recruiting
Tufts Medical Center | Boston, Massachusetts, 02111, United States Recruiting
University of Minnesota | Minneapolis, Minnesota, 55455, United States Recruiting
Duke University | Durham, North Carolina, 27705, United States Recruiting
Baylor College of Medicine/Texas Children's Hospital | Houston, Texas, 77030, United States Recruiting
Location Countries

United States

Verification Date

October 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: LentiGlobin BB305 Drug Product for SCD

Type: Experimental

Description: 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.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov