Clinical trial NCT04293185: A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease
Official title: A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the BB305 Lentiviral Vector in Subjects With Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Sickle Cell Disease
Lead sponsor: bluebird bio
Sponsor class: INDUSTRY
First posted: 2020-03-03
Enrollment: 35
Sex: ALL
Minimum age (years): 2
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 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) using bb1111 (also known as 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.
* In the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 protocol-defined VOEs in the 24 months prior to informed consent.
* 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).
* Female and male subjects of childbearing potential agree to use 1 method of highly effective contraception from Screening to at least 6 months after drug product infusion.
* Provision of written informed consent for this study by subject, or as applicable, subject's parent(s)/legal guardian(s).

Exclusion Criteria:

* Subjects for whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically appropriate per PI judgment and a willing, human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available.
* Severe cerebral vasculopathy, defined by any history of overt ischemic or hemorrhagic stroke, a history of abnormal transcranial Doppler (TCD) or TCD imaging (TCDI) for subjects ≤ 16 years of age (e.g. TCD velocity \>200 cm/sec) requiring ongoing chronic transfusions, a Screening TCD or TCDI velocity \> 200 cm/sec (central read), a Screening MRA showing \> 50% stenosis or occlusion in the circle of Willis (central read), or a Screening MRA showing the presence of Moyamoya (central read).
* Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotropic virus-1 (HTLV-1), 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 pRBC transfusion.
* Prior receipt of an allogeneic 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.
* Female subject is breastfeeding, pregnant or will attempt to become pregnant from Screening to at least 6 months after drug product infusion.
* 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.
* Presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) per Investigator's judgment.
* Presence of genetic mutations that result in the inactivation of 2 or more α-globin genes

Primary outcomes:
measure: VOE-CR
timeFrame: 6-18 months post-transplant
Secondary outcomes:
measure: sVOE-CR
timeFrame: 6-18 months post-transplant
measure: Proportion of subjects achieving Globin Response
timeFrame: 6-24 months post-transplant
measure: Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent
timeFrame: 1-24 months post-transplant
measure: 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.
timeFrame: 1-24 months post-transplant
measure: VOE-CR24
timeFrame: 6-24 months post-transplant
measure: sVOE-CR24
timeFrame: 6-24 months post-transplant
measure: sVOE-75
timeFrame: 1-24 months post-transplant
measure: Weighted average non-transfused total Hb
timeFrame: Month 6, 12, 18 and 24 post-transplant
measure: Weighted average HbS percentage of non-transfused total Hb
timeFrame: Month 6, 12, 18 and 24 post-transplant
measure: Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50%
timeFrame: Month 6, 12, 18 and 24 post-transplant
measure: Weighted average HbAT87Q percentage of non-transfused total Hb
timeFrame: Month 6, 12, 18 and 24 post-transplant
measure: Weighted average non-HbS percentage of non-transfused total Hb
timeFrame: Month 6, 12, 18 and 24 post-transplant
measure: Average and median of non-transfused total Hb
timeFrame: 1-24 months post-transplant
measure: Average and median of HbS percentage of non-transfused total Hb
timeFrame: 1-24 months post-transplant
measure: Average and median of HbAT87Q percentage of non-transfused total Hb
timeFrame: 1-24 months post-transplant
measure: Average and median of non-HbS percentage of non-transfused total Hb
timeFrame: 1-24 months post-transplant
measure: Change from baseline in absolute reticulocyte count
timeFrame: 1-24 months post-transplant
measure: Change from baseline in percent reticulocytes
timeFrame: 1-24 months post-transplant
measure: Change from baseline in percent erythrocytes
timeFrame: 1-24 months post-transplant
measure: Change from baseline in total bilirubin
timeFrame: 1-24 months post-transplant
measure: Change from baseline in haptoglobin
timeFrame: 1-24 months post-transplant
measure: Change from baseline in lactate dehydrogenase
timeFrame: 1-24 months post-transplant
measure: Change from baseline in ferritin
timeFrame: 1-24 months post-transplant
measure: Change from baseline in liver iron content
timeFrame: 1-24 months post-transplant
measure: Change from baseline in cardiac iron content (if assessed at baseline)
timeFrame: 1-24 months post-transplant
measure: Change from baseline in erythropoietin
timeFrame: 1-24 months post-transplant
measure: Change from baseline in serum transferrin receptor
timeFrame: 1 - 24 months post-transplant
measure: Change from baseline in annualized frequency of packed red blood cell (pRBC) transfusions
timeFrame: 6-24 months post-transplant
measure: Change from baseline in annualized volume of pRBC transfusions
timeFrame: 6-24 months post-transplant
measure: Change from baseline in TCD velocity at Month 12 and Month 24 (for subjects ≤ 16 years old at Informed Consent)
timeFrame: Month 12 and Month 24 post-transplant
measure: Change from baseline in meters walked during the 6-minute walk test
timeFrame: 1 - 24 months post-transplant
measure: Change from baseline in annualized number of SCD-related hospital admissions
timeFrame: 1 - 24 months post-transplant
measure: Change from baseline in annualized number of total days hospitalized
timeFrame: 1 - 24 months post-transplant
measure: Change from baseline in patient-reported quality of life, as measured by PROMIS-57 Version 2.1 for subjects ≥ 18 years of age and PROMIS Pediatric Profile/Parent Proxy Profile 49 Version 2.0 for subjects < 18 years of age
timeFrame: 1 - 24 months post-transplant
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Washington
country: United States
facility: Children's National Hospital
state: District of Columbia
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Houston
country: United States
facility: Baylor College of Medicine/Texas Children's Hospital
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University (VCU)
state: Virginia
Study officials:
affiliation: bluebird bio, Inc.
name: Anjulika Chawla, MD, FAAP
role: STUDY_DIRECTOR
References: