Severe sickle cell anemia and transfusion-dependent beta-thalassemia major. This study will enroll patients who are eligible for an allogeneic hematopoietic stem cell transplant (HSCT) but do not have a suitable, willing human leukocyte antigen (HLA)-identical sibling donor. MedDRA version: 14.1 Level: LLT Classification code 10055579 Term: Sickle-cell beta thalassemia System Organ Class: 100000004
Conditions
Interventions
Product Name: LentiGlobin BB305 Drug Product (autologous CD34 cells transduced w/ LentiGlobin BB305)
Pharmaceutical Form: Suspension for infusion
Sponsors
bluebird bio, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All subjects must: 1.Be between 5 and 35 years of age, inclusive. •Adult subjects (between 18 and 35 years of age, inclusive, at the time of consent) must be able to provide written consent. •For pediatric subjects (between 5 and 17 years of age, inclusive, at the time of consent), a competent parent or legal guardian must be able to provide written informed consent. When possible, involvement of the child >7 years of age in the decision is highly recommended, and written assent will be obtained and should be clearly documented. •Subjects aged 5 to 14 years require the approval from the Comité de Surveillance prior to enrollment. 2.Have severe SCA or transfusion dependent beta-ThalM, regardless of the genotype (e.g., ß0, ß+, ßE/ß0, ßS/ßS, ßS/ß0), with the diagnosis confirmed by Hb studies. Subjects with transfusion dependent beta-ThalM must be stable and maintained on an appropriate iron chelation regimen. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed RBCs. 3.Be candidates for HSCT. 4.Be willing and able, in the Investigator’s opinion, to comply with the study procedures outlined in the study protocol. If a pediatric subject, the subject’s parent/legal guardian also must be willing and able to comply with the study procedures outlined in the study protocol. 5.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 SCA also must: 6.Have 1 or more of the following poor prognostic risk factors despite having had adequate therapy (at least 4 months duration) with hydroxyurea (unless they were unable to tolerate hydroxyurea therapy): •Recurrent VOC and/or priapism (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program). •Presence of cerebral vasculopathy requiring a long term transfusion program (at least 6 months). •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. •Red cell alloimmunization (>2 antibodies). •Presence of sickle cell cardiomyopathy documented by Doppler echocardiography. •Recurrent acute chest syndrome (at least 2 episodes in the preceding year) defined by the presence of a new pulmonary infiltrate involving at least 1 complete lung segment (but excluding atelectasis) associated with at least 1 new symptom: chest pain, fever (>38.5°C), tachypnea, wheezing or cough not explained by infection. Subjects with a chronic oxygen saturation =65 years) no F.1.3.1 Number of subjects for this
Exclusion criteria
Exclusion criteria: All subjects must not meet any of the following: 1.Availability of a suitable, willing HLA identical sibling. 2.Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2), human T lymphotrophic virus 1 (HTLV 1), vesicular stomatitis virus G (VSV G) antibody or VSV G ribonucleic acid (RNA). 3.Clinically significant, active bacterial, viral, or fungal infection. 4.Contraindication to anesthesia for bone marrow harvesting. 5.Any prior or current malignancy, myeloproliferative or immunodeficiency disorder. 6.A white blood cell (WBC) count 3× upper limit of normal or the presence of histopathological evidence of liver cirrhosis 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 MRI. •Evidence of significant pulmonary hypertension. 15.Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician. 16.Participation in another clinical study with an investigational drug within 30 days of screening. 17.Subjects who have the desire to become a parent within the 27 month study period. 18.Prior receipt of gene therapy. 19.An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol. Subjects with beta-ThalM also must not: Be Pesaro Class III (poor compliance of iron chelation therapy, presence of hepatomegaly, and severe fibrosis) (Lucarelli et al., 2001).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Determine the safety, tolerability, and success of engraftment with autologous CD34+ hematopoietic stem cells transduced with LentiGlobin® BB305 lentiviral vector encoding the human beta-A-T87Q- globin gene and suspended in Albunorm™ (human serum albumin; HSA) 5% (i.e., LentiGlobin® BB305 Drug Product) after conditioning with Busulfex® (busulfan IV) in subjects with severe sickle cell anemia (SCA) or beta thalassemia major (beta ThalM).; Secondary Objective: I - Quantify gene transfer efficiency and expression: •Evaluate expression of beta-A-T87Q-globin chain in peripheral blood burst forming units erythroid (BFU-Es), reticulocytes, and red blood cells (RBCs). •Quantify the hematopoietic chimerism resulting from treatment with LentiGlobin® BB305 Drug Product (vector copy number [VCN]). II - Measure the effects of transplantation with LentiGlobin® BB305 Drug Product on the expression of disease-specific biological parameters and clinical events, including the volume of blood transfusions for both severe sickle cell anemia and beta-thalassemia major and, for subjects with severe sickle cell anemia, the number of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) events in each subject compared with the 2 year pre-treatment period. ; Primary end point(s): SAFETY ENDPOINTS: •Success and kinetics of HSC engraftment. •Incidence of transplant related mortality through 100 days post treatment. •Overall survival. •Detection of vector derived RCL in any subject. •Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia. •Monitoring of laboratory parameters and frequency and severity of clinical adverse events (AEs), as assessed by the United States (US) National Cancer Institute Common Terminology Criteria for Adverse Events (NC | — |
Countries
France
Contacts
Public ContactThierry Rousselot, Project Manager
NUVISAN ONCOLOGY SA
Outcome results
None listed