An Open Label Study Evaluating the Safety and Efficacy of Gene Therapy for Transfusion-dependent β-Thalassemia by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a LentiRed Lentiviral Vector (GMCN-508B Drug Product, Also Called LentiRed)
Overview
- Phase
- Early Phase 1
- Intervention
- Not specified
- Conditions
- Transfusion Dependent Beta-Thalassemia
- Sponsor
- First Affiliated Hospital of Guangxi Medical University
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Proportion of subjects whose red blood cells (RBC) transfusion requirement was reduced for ≥6 months after LentiRed Drug Product infusion, compared to previous 2-year transfusion records.
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a single-arm, open label, single-dose study in subjects with transfusion dependent β-thalassaemia. The study will evaluate the safety and efficacy of autologous CD34+ Human Hematopoietic Stem Cells that was transduced with LentiRed Lentivrial vector.
Detailed Description
Subject participation for this study will be 5 years.
Investigators
Yongrong Lai
MD, Director of Hematology Department of First Affiliated Hospital of Guangxi Medical University
First Affiliated Hospital of Guangxi Medical University
Eligibility Criteria
Inclusion Criteria
- •The subject himself/herself or one legal guardian/agent of the subject is required to fully understand the study and voluntarily sign a written informed consent.
- •Ages 5 to 35, no gender limitation.
- •The clinical diagnosis of TDT includes β0/β0, β+/β0, βE/β0 and β+/β+ genotypes. TDT was defined as severe anemia in patients with thalassemia (Hb persistent \<70 g/L), regular RBC transfusion and standard iron removal therapy to survive for life.
- •Karnofsky Level of Performance (KPS) score ≥70 in adult subjects and Lansky Level of Performance (LPS) score ≥70 in children subjects.
- •Subjects were determined to undergo autologous hematopoietic stem cell transplantation by the principle investigator.
- •Subjects must have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.
Exclusion Criteria
- •Hepatitis B virus (HBV) : HbsAg or HbcAb positive, nucleic acid test positive; Hepatitis C virus (HCV) : HCAb positive, nucleic acid test positive; Positive for Human immunodeficiency virus (HIV) antibody or Treponema pallidum (TP) specific antibody; Tuberculosis: positive interferon gamma release test.
- •A white blood cell (WBC) count \<3×10\^9/L and/or platelet count \<100×10\^9/L, splenectomy was performed before.
- •Uncured bleeding abnormalities.
- •Any previous or current malignancy, myeloproliferative disease, or immune deficiency disease.
- •Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndromes, hereditary non-polyposis colorectal cancer syndromes and familial adenomatous polyposis).
- •Previous hematopoietic stem cell transplantation (HSCT).
- •Advanced liver disease, defined as: 1) Baseline alanine aminotransferase (ALT) or direct bilirubin ≥3 normal upper limit (ULN), or 2) Liver biopsy demonstrating cirrhosis, any evidence of bridging fibrosis, or acute hepatitis.
- •Baseline estimated glomerular filtration rate (eGFR) \< 70 mL/min /1.73 m2, as determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation for ≥18 years of age, and Besides Schwartz Equation calculator \< 18 years of age.
- •Uncontrolled seizure disorder.
- •Diffusion capacity of Carbon monoxide dispersion (DLco) \<50% of predicted (corrected for hemoglobin and or alveolar ventilation, as clinically indicated ).
Outcomes
Primary Outcomes
Proportion of subjects whose red blood cells (RBC) transfusion requirement was reduced for ≥6 months after LentiRed Drug Product infusion, compared to previous 2-year transfusion records.
Time Frame: From time of drug product infusion up to 24 months
The annualized number of pRBC transfusions over the 2 year period prior to drug product infusion was compared to the annualized number of pRBC transfusions post drug product infusion and the percentage change was reported.
Number and proportion of subjects who maintained βA-T87Q-globin(HbAT87Q) at ≥2.0 g/dL for ≥ 6 months after LentiRed Drug Product infusion.
Time Frame: From time of drug product infusion up to 24 months
Percentage of participants with sustained production of \>=2.0 grams per deciliter (g/dL) of hemoglobin A (HbA) containing βA-T87Q-globin (HbAT87Q) for 6 months was reported.
Proportion of subjects who achieved transfusion independence, defined as an average Hb ≥ 9 g/dL without any pRBC transfusions for a continuous period of ≥ 6 months at any time during the study after LentiRed Drug Product infusion.
Time Frame: From time of drug product infusion up to 24 months
TI was defined as an average hemoglobin (Hb) \>= 9 g/dL without any packed red blood cells (pRBC) transfusions for a continuous period of \>=6 months at any time during the study after Drug Product infusion.
Secondary Outcomes
- Overall survival.(From time of drug product infusion up to 24 months)
- Detection of vector-derived replication competent lentivirus (RCL) in any subject.(From time of drug product infusion up to 24 months)
- Proportion of subjects who achieved transfusion independence, defined as an average Hb ≥ 9 g/dL without any pRBC transfusions for a continuous period of ≥ 3 months at any time during the study after LentiRed Drug Product infusion.(From time of drug product infusion up to 24 months)
- Incidence of transplant-related mortality through 100 days post drug product infusion.(Through 100 days post-Drug Product infusion)
- Average vector copy number (VCN) in cell populations from peripheral blood and bone marrow containing the integrated LentiRed lentiviral vector.(From time of drug product infusion up to 24 months)
- Proportion of subjects who achieved Neutrophil engraftment.(From time of drug product infusion up to 24 months)
- Therapeutic globin expression, as measured by assessing the ratio of βA-T87Q-globin to α -globin in whole blood, as well as the amount of βA-T87Q-globin to as a fraction of all β -chains in whole blood.(From time of drug product infusion up to 24 months)
- Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia.(From time of drug product infusion up to 24 months)
- Monitor of frequency of clinical adverse events (AEs).(From signing of informed consent to 24 months after the drug product infusion)