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A Phase I Clinical Trial for the Treatment of ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene

Phase 1
18 Years
Open (Enrolling)
Confirmed Diagnosis of ß-thalassemia Major

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Trial Information

A Phase I Clinical Trial for the Treatment of ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene

Inclusion Criteria:

- Subjects must be 18 years or older

- Subjects may be of either gender or of any ethnic background

- Subjects must have a confirmed diagnosis of ß-thalassemia major and have been
enrolled in a hypertransfusion program with a confirmed annual transfusion of ≥100
mL/kg/yr but < 200 mL/kg/yr, AND ≥ 8 transfusions of blood per year over a minimum of
two years.

- Patients must NOT have an HLA-matched sibling

- Patients must be off hydroxyurea (HU) or erythropoietin (EPO) treatment for at least
three months prior to entry onto the study

- Subjects must have a performance score of Karnofsky ≥70% at the time of entry into
the study.

- Subjects must have liver iron value of < 15 mg/g/dry weight Iron quantitation may be
performed by imaging such as T2*MRI or by biopsy

- Subjects must have no evidence of cirrhosis** of the liver. Fibrosis of the liver can
be tested by Fibroscan (47, 48, 49), or by liver biopsy. These should be performed
within approximately a one year period prior to entry onto the study.

- Subjects with an evaluation of cardiac function indicating:

- normal function on MUGA scan (Multiple Gated Acquisition scan) or other methodology.


- Patients must have a left ventricular ejection fraction (LVEF) of ≥ 60% and/or T2*MRI
cardiac evaluation with T2* ≥20 milliseconds

- Subjects with asymptomatic pulmonary function based on Lung Diffusion Testing DLCO
Test DLCO ≥ 50% of predicted (corrected for hemoglobin)

- Subjects with a determination of renal function based on: serum creatinine < than or
= to 1.5 mg/dL or if serum creatinine is outside the normal range, then CrCl >
60-ml/min/1.73 m2

- Subjects must have adequate hepatic function based on:

- < 3 x ULN ALT and

- < 2.0 total serum bilirubin (unless secondary to hemolysis)

- Patients must be available for follow-up evaluations at 30, 60, 180 days post BMT and
yearly thereafter indefinitely.

- The possibility of unrelated donor stem cell transplantation will be discussed
with patients, and a "preliminary" search for an unrelated donor may be done at
the request of the patient. However, the finding of a potential HLA-matched
unrelated donor will not exclude the patient from participating into this

- As the inclusion criteria are more specific than the Lucarelli/Pesaro
thalassemia pre-transplant classification (Class 1,2 or 3 according to
presence or absence of fibrosis, adequate chelation and/or hepatomegaly),
the criteria stated above will be used in lieu of the Lucarelli/Pesaro

Exclusion Criteria:

- Active infections including Hepatitis B and Hepatitis C***,

- Active infections including HTLV 1 and 2, and HIV 1 and 2

- Patients with treated HLTV or HIV

- Diabetes Mellitus

- Bone Marrow myelodysplasia and/or chromosomal abnormalities

- Female patient pregnant or breast feeding

- Patients with uncontrolled seizure disorders

- Patients with severe pulmonary hypertension Tricuspid Jet velocity > 2.5 m/sec

- Family history of familial cancer syndromes (leukemia, breast, ovarian, colorectal,

*** Definition of active Hepatitis C include:

- Positive HCV RNA Viral load by quantitative PCR testing Or if Negative HCV RNA viral
load BUT on antiviral treatment

- Liver biopsy with pathologic evidence of

- Necrosis and inflammation around the portal areas - piecemeal necrosis or interface
hepatitis or necrosis of hepatocytes and focal inflammation in the liver parenchyma.

- Inflammatory cells in the portal areas ("portal inflammation").

- Fibrosis, with early stages being confined to the portal tracts, intermediate stages
being expansion of the portal tracts and bridging between portal areas or to the
central area, and late stages being frank cirrhosis characterized by architectural
disruption of the liver with fibrosis and regeneration.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

of transplanted autologous CD34+ hematopoietic cells that are transduced ex vivo with TNS9.3.55 and transplanted in subjects with ß-thalassemia major conditioned with a reduced-intensity non-myeloablative preparative regimen. The occurrence of insertional oncogenesis, which will be investigated by monitoring peripheral blood cell counts and leukocyte clonality using FACS analysis, qPCR for vector. copy number, LAM-PCR and/or 454 sequencing; The generation of a replication-competent lentivirus (RCL). The safety of a low dose non-myeloablative conditioning regimen

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Farid Boulad, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2012

Completion Date:

July 2014

Related Keywords:

  • Confirmed Diagnosis of ß-thalassemia Major
  • G-CSF
  • CliniMACS-CD34 Reagent System
  • Blood transfusion
  • 10-164
  • Autologous CD34+ cells transduced with TNS9.3.55, a lentiviral vector encoding the human β-globin gene
  • Beta-Thalassemia
  • Thalassemia



Memorial Sloan-Kettering Cancer Center New York, New York  10021