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A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT02140554
Recruitment Status : Active, not recruiting
First Posted : May 16, 2014
Last Update Posted : August 19, 2019
Sponsor:
Information provided by (Responsible Party):
bluebird bio

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Genetic: LentiGlobin BB305 Drug Product Biological: Plerixafor Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : August 2014
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Plerixafor

Arm Intervention/treatment
Experimental: Group A

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

Genetic: LentiGlobin BB305 Drug Product
LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.
Other Name: autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene

Experimental: Group B

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

Genetic: LentiGlobin BB305 Drug Product
LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.
Other Name: autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene

Biological: Plerixafor
Plerixafor is administered by subcutaneous injection prior to apheresis.

Experimental: Group C
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.
Genetic: LentiGlobin BB305 Drug Product
LentiGlobin BB305 Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.
Other Name: autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene

Biological: Plerixafor
Plerixafor is administered by subcutaneous injection prior to apheresis.




Primary Outcome Measures :
  1. 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 [ Time Frame: 1-24 months post-transplant ]
    Subjects must meet these criteria for a continuous period of ≥6 months at any time after drug product infusion (starting ≥60 days after last pRBC transfusion)


Secondary Outcome Measures :
  1. severe vaso-occlusive event (sVOE)-75 [ Time Frame: 1-24 months post-transplant ]
    A 75% reduction in annualized severe VOEs in the 24 months after drug product treatment versus the 24 months prior to Informed Consent

  2. Annualized sVOE [ Time Frame: 1-24 months post-transplant ]
    A reduction in the annualized number of severe VOEs in the 24 months after drug product infusion as compared to the 24 months prior to informed consent

  3. sVOE-CR [ Time Frame: 6 - 24 months post-transplant ]
    Complete resolution of severe VOE

  4. sVOE-90 [ Time Frame: 24 months post-transplant ]
    A 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

  5. Success and kinetics of HSC engraftment [ Time Frame: 1-24 months post-transplant ]
    Defined as 3 consecutive ANC ≥0.5 × 109/L laboratory values obtained on different days by Day 43 post-infusion

  6. Incidence of acute (≥Grade 2) and/or chronic graft-versus-host disease (GVHD) [ Time Frame: 1 - 24 months post-transplant ]
    As defined in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02140554


Locations
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United States, Alabama
University of Alabama
Birmingham, Alabama, United States
United States, California
Oakland, California, United States
United States, Georgia
Atlanta, Georgia, United States, 30322
United States, Illinois
Chicago, Illinois, United States
United States, Maryland
Bethesda, Maryland, United States
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States
United States, New York
New York, New York, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States
United States, South Carolina
Charleston, South Carolina, United States
Sponsors and Collaborators
bluebird bio
Investigators
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Study Director: Jean-Antoine Ribeil, MD, PhD bluebird bio, Inc.

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Responsible Party: bluebird bio
ClinicalTrials.gov Identifier: NCT02140554     History of Changes
Other Study ID Numbers: HGB-206
First Posted: May 16, 2014    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Hematologic Diseases
Genetic Diseases, Inborn
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hemoglobinopathies
Plerixafor octahydrochloride
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents