Overview

This trial is active, not recruiting.

Conditions beta-thalassemia major, sickle cell disease
Treatment lentiglobin bb305 drug product
Phase phase 1/phase 2
Sponsor bluebird bio
Start date July 2013
End date December 2017
Trial size 7 participants
Trial identifier NCT02151526, 2012-000695-42, HGB-205

Summary

This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to subjects with either beta-thalassemia major or severe sickle cell disease (SCD).

United States No locations recruiting
Other countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
LentiGlobin BB305 Drug Product (autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q-globin gene)
lentiglobin bb305 drug product
autologous CD34+ hematopoietic stem cells (HSCs) transduced with the LentiGlobin BB305 lentiviral vector encoding the human beta-A-T87Q globin gene Subjects with beta-thalassemia major will undergo HSC procurement by bone marrow harvest or apheresis after mobilization with filgrastim, a granulocyte-colony stimulating factor (G-CSF), alone or in combination with plerixafor, as decided by the clinical transplant team. Stem cell mobilization by is contraindicated in sickle cell disease (SCD), as it could induce a sickle cell crisis; thus, procurement of HSCs for subjects with severe SCD will be conducted by bone marrow harvest.

Primary Outcomes

Measure
Success and kinetics of hematopoietic stem cell (HSC) engraftment
time frame: 1-24 months post-transplant
Incidence of transplant related mortality through 100 days post treatment
time frame: 1-24 months post-transplant
Overall survival
time frame: 1-24 months post-transplant
Detection of vector derived replication-competent lentivirus (RCL) in any subject
time frame: 1-24 months post-transplant
Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia
time frame: 1-24 months post-transplant
Monitoring of laboratory parameters and frequency and severity of clinical AEs
time frame: 1-24 months post-transplant

Secondary Outcomes

Measure
Quantify gene transfer efficiency and expression by evaluation
time frame: 1-24 months post-transplant
Quantify gene transfer efficiency and expression by evaluation
time frame: 1-24 months post-transplant
Efficacy
time frame: 1-24 months post-transplant
Efficacy
time frame: 1-24 months post-transplant

Eligibility Criteria

Male or female participants from 5 years up to 35 years old.

Inclusion Criteria

  • Be between 5 and 35 years of age, inclusive.
  • Have severe sickle cell disease (SCD) or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs).
  • Be eligible for allogeneic HSC transplant based on institutional medical guidelines, but without a matched related donor.
  • Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history. Subjects with severe SCD also must:
  • Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated.
  • Have 1 or more of the following poor prognostic risk factors:
    • Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
    • Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
    • Stroke without any severe cognitive disability.
    • Osteonecrosis of 2 or more joints.
    • Anti-erythrocyte alloimmunization (>2 antibodies).
    • Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
    • Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever [>38.5°C], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Subjects with a chronic oxygen saturation <90% (excluding periods of SCD crisis) or carbon monoxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.

Exclusion Criteria

  • Availability of a willing 10 /10 matched HLA identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comité de Surveillance following a review of the case.
  • Clinically significant, active bacterial, viral, fungal, or parasitic infection.
  • Contraindication to anesthesia for bone marrow harvesting.
  • Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.
  • A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L.
  • History of major organ damage including:
    • Liver disease, with transaminase levels >3× upper limit of normal.
    • This observation will not be exclusionary if a liver biopsy shows no evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis.
    • Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy.
    • Heart disease, with a left ventricular ejection fraction <25%.
    • Kidney disease with a calculated creatinine clearance <30% normal value.
    • Severe iron overload, which in the opinion of the physician is grounds for exclusion.
    • A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
    • Evidence of clinically significant pulmonary hypertension requiring medical intervention.

Additional Information

Official title A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the Beta-Hemoglobinopathies (Sickle Cell Disease and Beta-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral Beta-A-T87Q Globin Vector (LentiGlobin BB305 Drug Product)
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by bluebird bio.