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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

May 14, 2014
May 16, 2014
November 9, 2018
August 2014
January 2021   (Final data collection date for primary outcome measure)
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)
Safety [ Time Frame: 1-24 months post-transplant ]
Safety will be evaluated by the following:
  • success and kinetics of hematopoietic stem cell (HSC) engraftment
  • incidence of treatment-related mortality
  • incidence of mortality through 2 years after drug product infusion
  • detection of vector-derived replication competent lentivirus (RCL) in any subject
  • characterization of events of insertional mutagenesis leading to malignancy
  • monitoring of laboratory parameters and frequency and severity of clinical AEs, as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03
Complete list of historical versions of study NCT02140554 on ClinicalTrials.gov Archive Site
  • 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 ]
  • 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
  • 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)
Clinical efficacy will be evaluated by comparing the frequency of clinical events secondary to sickle cell disease [ Time Frame: 1-24 months post-transplant ]
Efficacy will be evaluated by the following:
  • severe vaso-occlusive crisis (VOC). A severe VOC is defined as an episode of pain lasting more than 2 hours severe enough to require care at a medical facility. Priapism that lasts more than 2 hours and requires care at a medical facility is considered a severe VOC
  • acute chest syndrome events, defined as an acute event with pneumonia-like symptoms and the presence of a new pulmonary infiltrate
  • strokes or transient ischemic attacks
Not Provided
Not Provided
 
A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe Sickle Cell Disease
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
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.
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.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Sickle Cell Disease
  • 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 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

    Intervention: Genetic: LentiGlobin BB305 Drug Product
  • 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

    Interventions:
    • Genetic: LentiGlobin BB305 Drug Product
    • Biological: Plerixafor
  • 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.
    Interventions:
    • Genetic: LentiGlobin BB305 Drug Product
    • Biological: Plerixafor
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
50
8
January 2021
January 2021   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
12 Years to 50 Years   (Child, Adult)
No
Contact: bluebird bio +1-339-499-9300 clinicaltrials@bluebirdbio.com
United States
 
 
NCT02140554
HGB-206
Yes
Not Provided
Not Provided
bluebird bio
bluebird bio
Not Provided
Study Director: Jean-Antoine Ribeil, MD, PhD bluebird bio, Inc.
bluebird bio
November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP