A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease
A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe Sickle Cell Disease
Sponsors
Source
bluebird bio
Oversight Info
Has Dmc
Yes
Brief Summary
This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in
approximately 50 adults and adolescents with severe SCD. The study will evaluate
hematopoietic stem cell (HSC) transplantation (HSCT) using LentiGlobin BB305 Drug Product.
Detailed Description
Subject participation for this study will be 2 years post-transplant. Subjects who enroll in
this study will be asked to participate in a subsequent long-term follow up study that will
monitor the safety and efficacy of the treatment they receive for up to 13 years
post-transplant.
Overall Status
Active, not recruiting
Start Date
2014-08-01
Completion Date
2022-02-01
Primary Completion Date
2022-02-01
Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
a. Weighted average HbAT87Q percentage of total Hb ≥30% AND b. Weighted average total Hb increase of ≥3 g/dL compared to baseline total Hb OR weighted average total Hb ≥10 g/dL |
1-24 months post-transplant |
Secondary Outcome
Measure |
Time Frame |
severe vaso-occlusive event (sVOE)-75 |
1-24 months post-transplant |
Annualized sVOE |
1-24 months post-transplant |
sVOE-CR |
6 - 24 months post-transplant |
sVOE-90 |
24 months post-transplant |
Success and kinetics of HSC engraftment |
1-24 months post-transplant |
Incidence of acute (≥Grade 2) and/or chronic graft-versus-host disease (GVHD) |
1 - 24 months post-transplant |
Enrollment
50
Condition
Intervention
Intervention Type
Genetic
Intervention Name
Description
LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.
Arm Group Label
Group A
Group B
Group C
Other Name
autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene
Intervention Type
Biological
Intervention Name
Description
Plerixafor is administered by subcutaneous injection prior to apheresis.
Arm Group Label
Group B
Group C
Eligibility
Criteria
Inclusion Criteria:
1. Be ≥12 and ≤50 of age at time of consent.
2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype.
3. Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD
(e.g.,pain management plan) have experienced at least 4 severe VOEs in the 24 months
prior to informed consent.
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.
4. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status
of ≥60 (<16 years of age).
5. Have either experienced hydroxyurea (HU) failure at any point in the past or must have
intolerance to HU (defined as patient being unable to continue to take HU per PI
judgement).
6. Have been treated and followed for at least the past 24 months prior to Informed
Consent in medical center(s) that maintained detailed records on SCD history.
Exclusion Criteria:
1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2),
hepatitis B virus (HBV), or hepatitis C (HCV).
2. Clinically significant and active bacterial, viral, fungal, or parasitic infection.
3. Inadequate bone marrow function, as defined by an absolute neutrophil count of <
1000/µL (< 500/µL for subjects on HU treatment) or a platelet count < 120,000/µL
(without hypersplenism).
4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke;
abnormal transcranial Doppler [≥200 cm/sec] needing chronic transfusion; or occlusion
or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with
radiologic evidence of silent infarction in the absence of any of the above criteria
would still be eligible
5. Advanced liver disease, defined as:
1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin
value >3× the upper limit of normal (ULN), or
2. Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of
arising from liver disease, or
3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of
cirrhosis, or
4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive
evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up
liver biopsy in subjects ≥18 years of age. In subjects <18 years of age, these
MRI findings are exclusionary, unless in the opinion of the Investigator, a liver
biopsy could provide additional data to confirm eligibility and would be safe to
perform. If a liver biopsy is performed based on MRI findings, any evidence of
cirrhosis, bridging fibrosis, or significant active hepatitis will be
exclusionary.
6. 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.
7. Any prior or current malignancy or immunodeficiency disorder, except previously
treated, non-life threatening, cured tumors such as squamous cell carcinoma of the
skin.
8. Prior receipt of an allogeneic transplant.
9. Immediate family member with a known or suspected Familial Cancer Syndrome.
10. Diagnosis of significant psychiatric disorder of the subject that, in the
Investigator's judgment, could seriously impede the ability to participate in the
study.
11. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception
for fertile subjects.
12. Participation in another clinical study with an investigational drug within 30 days of
Screening.
13. Prior receipt of gene therapy.
14. Patients needing curative anticoagulation therapy during the period of conditioning
through platelet engraftment (patients on prophylactic doses of anticoagulants are
eligible).
15. Unable to receive RBC transfusion.
Gender
All
Minimum Age
12 Years
Maximum Age
50 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
Jean-Antoine Ribeil, MD, PhD |
Study Director |
bluebird bio, Inc. |
Location
Facility |
University of Alabama Birmingham Alabama United States |
Oakland California United States |
Atlanta Georgia 30322 United States |
Chicago Illinois United States |
Bethesda Maryland United States |
Hackensack University Medical Center Hackensack New Jersey United States |
New York New York United States |
Philadelphia Pennsylvania United States |
Charleston South Carolina United States |
Location Countries
Country
United States
Verification Date
2019-08-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Has Expanded Access
No
Condition Browse
Number Of Arms
3
Intervention Browse
Mesh Term
Plerixafor octahydrochloride
Arm Group
Arm Group Label
Group A
Arm Group Type
Experimental
Description
Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of LentiGlobin BB305 Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by bone marrow harvest transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.
*No Longer Recruiting
Arm Group Label
Group B
Arm Group Type
Experimental
Description
Group B1:
Subjects will have rescue cells collected by bone marrow harvest, and will receive treatment of LentiGlobin BB305 Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by bone marrow harvest transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.
*No Longer Recruiting
Group B2:
Plerixafor mobilization and apheresis will be used for collection of rescue cells and exploratory manufacturing development. Subjects will receive treatment of LentiGlobin BB305 Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by bone marrow harvest transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.
*No Longer Recruiting
Arm Group Label
Group C
Arm Group Type
Experimental
Description
Plerixafor mobilization and apheresis will be used for collection of rescue cells, and subjects will receive treatment of LentiGlobin BB305 Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene.
Firstreceived Results Date
N/A
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
May 14, 2014
Study First Submitted Qc
May 14, 2014
Study First Posted
May 16, 2014
Last Update Submitted
August 16, 2019
Last Update Submitted Qc
August 16, 2019
Last Update Posted
August 19, 2019
ClinicalTrials.gov processed this data on December 09, 2019
Conditions
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conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.