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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 : Recruiting
First Posted : May 16, 2014
Last Update Posted : November 9, 2018
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.

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 : January 2021
Estimated Study Completion Date : January 2021

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. A 75% reduction in annualized severe VOEs in the 24 months after drug product treatment versus the 24 months prior to Informed Consent [ Time Frame: 1-24 months post-transplant ]
  2. 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

  3. 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)



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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, hydroxyurea) have experienced severe VOEs as defined below: at least 4 episodes requiring hospital inpatient admission in the 24 months prior to informed consent. 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.

    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 hospital inpatient admission over 24 hours and including:

    1. An episode of acute pain with no medically determined cause other than a vaso-occlusive event requiring admission over 24 hours
    2. Acute chest syndrome (ACS), defined by an acute event with pneumonia-like symptoms (e.g., chest pain, fever [>38.5°C], tachypnea, wheezing or cough, findings upon lung auscultation,) and the presence of a new pulmonary infiltrate consistent with acute chest syndrome.
    3. Acute hepatic sequestration, defined by a sudden increase in liver size associated with pain in the right upper quadrant, abnormal results of liver-function test not due to biliary tract disease, and reduction in hemoglobin concentration by at least 2 g/dL below the baseline value
    4. Acute splenic sequestration, defined as sudden enlargement of the spleen and reduction in hemoglobin concentration by at least 2 g/dL below the baseline value
    5. Acute priapism: defined as a sustained, unwanted painful erection lasting more than 2 hours and requiring care at a medical facility (with or without hospitalization)
  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 HU failure at any point in the past or must have intolerance to HU (defined as inability to be maintained on an adequate dose of HU due to marrow suppression or severe drug-induced toxicity [e.g. gastrointestinal distress, fatigue]).
  6. Have been treated and followed for at least the past 24 months 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 hydroxyurea 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
  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


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

Locations
United States, California
Recruiting
Oakland, California, United States
United States, Georgia
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
United States, Illinois
Recruiting
Chicago, Illinois, United States
United States, Maryland
Recruiting
Bethesda, Maryland, United States
United States, New York
Recruiting
New York, New York, United States
United States, Pennsylvania
Recruiting
Philadelphia, Pennsylvania, United States
United States, South Carolina
Recruiting
Charleston, South Carolina, United States
Sponsors and Collaborators
bluebird bio
Investigators
Study Director: Jean-Antoine Ribeil, MD, PhD bluebird bio, Inc.

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: November 9, 2018
Last Verified: November 2018

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
JM 3100
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents