Beta-Thalassemia
Conditions
Brief summary
The goal of this open label, single-arm clinical study is to learn about the safety and efficacy of base-edited autologous hematopoietic stem cell transplantation(CS-101) in treating patients with β-thalassemia major.
Detailed description
CS-101 is an autologous CD34+ cell suspension modified by ex vivo base editing technology, removing the inhibitory effect of BCL11A on the γ-globin coding gene, inducing the production of γ-globin chains, increasing the concentration of fetal hemoglobin (HbF) in the blood, compensating for the loss of adult hemoglobin (HbA) to treat transfusion-dependent type/ Major β - thalassemia. The therapy addresses two major challenges in the treatment of the disease: lack of matching donors and graft-versus-host responses commonly seen in allogeneic hematopoietic stem cell transplantation. The study consists of the following five phases: Screening phase: Sign informed consent, complete screening assessments, and confirm the eligibility for enrollment; Baseline: check the subject's baseline status; Mobilization, collection and manufacturing phase: mobilize, collect autologous CD34+ cells and manufacture, release and transport CS-101 product; Conditioning and treatment phase: including myeloablation and CS-101 product infusion; Follow-up phase: 180 days post-infusion.
Interventions
BIOLOGICALCS-101 injection
Autologous CD34+ hematopoietic stem cell suspension modified by in vitro base editing technique
Sponsors
Children's Hospital of Fudan University
CorrectSequence Therapeutics Co., Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* 3 to 17 years old(inclusive) male or female subjects at the time of informed consenting * Diagnosis of β-thalassemia, genotypes include but are not limited to β+β0, βEβ0, β0β0, etc * Generally in good condition, Karnofsky performance score≥60 points for subjects≥16 years old at the time of autologous hematopoietic stem cell collection, or Lansky Play-Performance score≥60 points for subjects under 16 years old, or equivalent clinical evaluation as the investigator site's common practice * For female subjects of childbearing potential: use effective contraceptive measures for at least 1 month prior to screening and agree to continue using such measures for contraception throughout the study * For male subjects who have a potential ability to father a child: use condoms or other methods continuously from the start of mobilization to ensure effective contraception for sexual partners during the study period
Exclusion criteria
* Treatment with other investigational medications or other experimental interventions 30 days prior to signing informed consent or within 6 half-lives of the drug, whichever is longer. * Subjects who have received or are receiving thalidomide and/or Luspatercept, when their drug-drug interaction on the efficacy and safety of CS-101 cannot be ruled out, unless at least there are 3 test results showing the total hemoglobin level before transfusion is below 9g/dL in the past 6 months before screening. * Previously received allogeneic hematopoietic stem cell transplantation or gene(edited) therapy. * Subjects have available related fully matching donors and are eligible and prepared for allogeneic hematopoietic stem cell transplantation. * Subjects with coexisting α-thalassemia and more than 2 deletions or non-deletional mutations in the α-globin chain coding genes. * Known to be allergic to drugs used during autologous hematopoietic stem cell transplantation (including but not limited to granulocyte colony-stimulating factor, busulfan, dextran), excipients(such as dimethyl sulfoxide), or instruments(such as intravenous catheters) as determined by the investigator are deemed unsuitable to participate in this study. * Those with active infections, including but not limited to: HIV, hepatitis B, hepatitis C, cytomegalovirus, Epstein-Barr virus and treponema pallidum test positive, or known tuberculosis, parasitic infection, etc. who are judged by the investigator to be unsuitable to participate in this study * Echocardiography results with ejection fraction below 45% * Subjects who are febrile (temperature over 37.3° C) should be held back from enrolment. * Advanced liver disease, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) \>3 × upper limit of normal (ULN) or baseline International Normalized Ratio (INR) \>1.5 × ULN * MRI during the screening period showed heavy iron overload and is judged by the investigator to be unable to participate in the study. * Patients with past/present history of cancer * Known neurological disorders, psychological problems or mental illness, and is judged by the investigator to be unable to cooperate with the study procedures * Known history of uncontrolled epileptic seizures and is judged by the investigator to be unfit to participate in this study * Known history of other serious cardiovascular, pulmonary, renal diseases, digestive tract conditions, liver diseases and / or other conditions, etc., and are judged by the investigator to be intolerable or inappropriate for autologous hematopoietic stem cell mobilization, collection, and myeloablative conditioning and infusion * Pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of engraftment | within 42 days post-CS-101 infusion | Subjects with engraftment is defined as neutrophil engrafted |
| Time to neutrophil and platelet engraftment | Days post-CS-101 infusion | Time to neutrophil engraftment is defined as first day of 3 consecutive measurements of absolute neutrophil count≥0.5×10\^9/L on three different days; Time to platelet engraftment is defined as first day of 3 consecutive measurements of absolute platelet count≥20×10\^9/L on three different days and without platelet transfusion |
| Occurrence of transplant-related death | baseline to 100 days post-CS-101 infusion | — |
| Occurrence of all-cause death | From signing informed consent to 180 days post-CS-101 infusion | — |
| Occurrence of achieving transfusion reduction for at least 3 consecutive months | From 3 months post -CS-101 infusion to 3 months post -CS-101 infusion | — |
| Frequency and severity of adverse events(AEs) as assessed by CTCAE v5.0 | From signing informed consent to 180 days post-CS-101 infusion | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to last red blood cell(RBC) transfusion | Days post-CS-101 infusion | — |
| Change in total hemoglobin(Hb) concentration over time | up to 180 days post-CS-101 infusion | — |
| Change in fetal hemoglobin(HbF) concentration over time | up to 180 days post-CS-101 infusion | — |
| Chimerism level in Peripheral blood and bone marrow | up to 180 days post-CS-101 infusion | Proportion of alleles with intended genetic modification in peripheral blood leukocytes and bone marrow over time |
| Occurrence of achieving transfusion independence for at least 3 consecutive months | From 3 months up to 180 days post-CS-101 infusion | — |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORXiaowen Zhai, M.D.
Children's Hospital of Fudan University
Outcome results
None listed