A Study Evaluating the Safety and Efficacy of LentiRed Drug Product in Transfusion-dependent β-Thalassemia [TDT]

Официальное название

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)

Обзор

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.

Подробное описание

Subject participation for this study will be 5 years.

Вмешательства

• Генная терапия GMCN-508B (LentiRed)
  LentiRed Drug Product is administered by intravenous infusion following myeloablative conditioning with busulfan.

Первичные конечные точки

• 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. [Срок оценки: From time of drug product infusion up to 24 months]
• Number and proportion of subjects who maintained βA-T87Q-globin(HbAT87Q) at ≥2.0 g/dL for ≥ 6 months after LentiRed Drug Product infusion. [Срок оценки: From time of drug product infusion up to 24 months]
• 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. [Срок оценки: From time of drug product infusion up to 24 months]

Вторичные конечные точки (9)

• 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. [Срок оценки: From time of drug product infusion up to 24 months]
• Proportion of subjects who achieved Neutrophil engraftment. [Срок оценки: From time of drug product infusion up to 24 months]
• Incidence of transplant-related mortality through 100 days post drug product infusion. [Срок оценки: Through 100 days post-Drug Product infusion]
• Overall survival. [Срок оценки: From time of drug product infusion up to 24 months]
• Detection of vector-derived replication competent lentivirus (RCL) in any subject. [Срок оценки: From time of drug product infusion up to 24 months]
• Characterization of events of insertional mutagenesis leading to clonal dominance or leukemia. [Срок оценки: From time of drug product infusion up to 24 months]
• Monitor of frequency of clinical adverse events (AEs). [Срок оценки: From signing of informed consent to 24 months after the drug product infusion]
• 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. [Срок оценки: From time of drug product infusion up to 24 months]
• Average vector copy number (VCN) in cell populations from peripheral blood and bone marrow containing the integrated LentiRed lentiviral vector. [Срок оценки: From time of drug product infusion up to 24 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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 ).
• A cardiac T2\* <20 ms by magnetic resonance imaging (MRI).
• Severe iron overload, which in the opinion of the physician is grounds for exclusion.
• Clinically significant pulmonary hypertension.
• Participation in another clinical study with an investigational drug within 30 days of screening.
• Failure to obtain appropriate informed consent.
• Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician or investigator.
• Contraindications to the conditioning regimen.
• Prior receipt of genetic stem cell therapy.
• Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study.
• Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects. Females of child-bearing potential are required to use effective contraception from the screening period until at least 6 months after drug product infusion. Male subjects are also required to use effective contraception (including condoms) from the screening period until at least 6 months after drug product infusion.
• Live vaccines were administered within 6 weeks prior to screening.
• Known history of hypersensitivity to the ingredients used in the trial.
• An assessment by the investigator that the subject would not comply with the study procedures outlined in the protocol.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• The affiliated hospital of guangxi medical university — Nanning

Идентификаторы

NCT: NCT05762510 · 2021-1101-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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