Clinical trial NCT01745120: A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in β-Thalassemia Major Participants
Official title: A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With β-Thalassemia Major by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: β-thalassemia Major
Keywords: gene therapy
β thalassemia
hemoglobin
anemia
CD34
Lead sponsor: bluebird bio
Sponsor class: INDUSTRY
First posted: 2012-12-07
Enrollment: 19
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a non-randomized, open label, multi-site, single-dose, phase 1/2 study in up to 18 participants (including at least 3 adolescents between 12 and 17 years of age, inclusive) with β-thalassemia major. The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product \[autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene\].

Detailed description: Subject participation for this study will be 2 years. 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.

Eligibility criteria: Inclusion criteria:

* Participants between 12 and 35 years of age, inclusive, at the time of consent/assent, and able to provide written consent/assent, if applicable.
* Diagnosis of β-thalassemia major and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years.
* Eligible for allogeneic bone marrow transplant.
* Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

Exclusion criteria:

* Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2).
* A white blood cell (WBC) count \<3 × 10\^9/L, and / or platelet count \<100 × 10\^9/L if not due to hypersplenism.
* Uncorrected bleeding disorder.
* Any prior or current malignancy or myeloproliferative or immunodeficiency disorder.
* Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome and familial adenomatous polyposis).
* Receipt of an allogeneic transplant.
* Advanced liver disease, including persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value \>3 × the upper limit of normal, liver biopsy demonstrating cirrhosis, extensive bridging fibrosis, or active hepatitis.
* Kidney disease with a calculated creatinine clearance \<30% normal value.
* Uncontrolled seizure disorder.
* Diffusion capacity of carbon monoxide (DLco) \<50% of predicted (corrected for hemoglobin).
* A cardiac T2\* \<10 ms by magnetic resonance imaging (MRI).
* Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion.
* Clinically significant pulmonary hypertension, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen.
* Participation in another clinical study with an investigational drug within 30 days of Screening.
* Any prior or current malignancy or myeloproliferative disorder.
* Prior receipt of gene therapy.

Primary outcomes:
measure: Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing βA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24
timeFrame: Month 18 to Month 24
measure: Percentage of Participants Who Achieved Transfusion Independence (TI)
timeFrame: From time of drug product infusion up to 24 months
Secondary outcomes:
measure: Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24
timeFrame: Month 18, Month 24
measure: Duration of Transfusion Independence (TI)
timeFrame: From time of drug product infusion up to 24 months
measure: Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI)
timeFrame: From time of drug product infusion up to 24 months
measure: Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)
timeFrame: From time of drug product infusion up to 24 months
measure: Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)
timeFrame: From time of drug product infusion up to 24 months
measure: Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24
timeFrame: Baseline, Month 24
measure: Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24
timeFrame: Baseline, Month 24
measure: Weighted Average Nadir Hemoglobin (Hb)
timeFrame: Baseline, Month 6 to Month 24
measure: Number of Participants With Successful Neutrophil Engraftment
timeFrame: From time of drug product infusion up to 24 months
measure: Time to Neutrophil Engraftment
timeFrame: From time of drug product infusion up to 24 months
measure: Number of Participants With Successful Platelet Engraftment
timeFrame: From time of drug product infusion up to 24 months
measure: Time to Platelet Engraftment
timeFrame: From time of drug product infusion up to 24 months
measure: Transplant-related Mortality
timeFrame: Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion
measure: Overall Survival
timeFrame: From time of drug product infusion up to 24 months
measure: Percentage of Participants Detected With Replication-competent Lentivirus (RCL)
timeFrame: From time of drug product infusion up to 24 months
measure: Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution
timeFrame: From time of drug product infusion up to 24 months
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From signing of informed consent to 24 months after the drug product infusion
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Oakland
country: United States
state: California
city: Chicago
country: United States
state: Illinois
city: Philadelphia
country: United States
state: Pennsylvania
city: Sydney
country: Australia
city: Bangkok
country: Thailand
Study officials:
affiliation: bluebird bio
name: Mohammed Asmal, MD
role: STUDY_DIRECTOR
References:
citation: Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479-1493. doi: 10.1056/NEJMoa1705342.