Transfusion-dependent Beta-Thalassemia
Conditions
Keywords
Beta-Thalassaemia, Hematopoietic Stem-Cell Transplantation
Brief summary
This is a non-randomized, open-label, single-dose study. The aim of this study is to evaluate the safety and efficacy of the treatment with lentiviral vector encoding βA-T87Q-globin gene transduced autologous hematopoietic stem cells in subjects with transfusion-dependent β-thalassemia.
Detailed description
Subject participation for this study will be 24 months. Subjects who enroll in this study will be asked to participate in a subsequent 13-year follow-up for gene therapy products.
Interventions
Transplant of auto-HSC transduced with lentiviral vector encoding βA-T87Q-globin gene.
Sponsors
R&D Kanglin Biotech
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Male or female age between 3-35 years * Diagnosis of transfusion-dependent β-thalassemia and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years * Documented baseline, or pretransfusion, Hb level≤7 g/dL * Karnofsky performance status ≥70 for subjects≥16 years of age; Lansky performance status of ≥70 for subjects\<16 years of age * Eligible to undergo auto-HSCT * Willing and able to follow the research procedures and conditions, with good compliance * Willing to receive at least the 2 years follow-up and maintain detailed medical records, including transfusion history * Subject and/or legal guardians voluntarily participated in this clinical trial and signed the informed consent form, and can complete all follow-up in accordance with the protocol requirements
Exclusion criteria
* Subjects positive with the following etiological tests: human immunodeficiency virus(HIV-1-2), human cytomegalovirus (HCMV-DNA), EB virus (EBV-DNA), HBV (HBsAg/HBV-DNA positive), HCV antibody (HCV-Ab), Treponema pallidum antibody (TP-Ab) * Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the clinical investigator * Contraindication to bone marrow collection * Any prior or current malignancy or myeloproliferative or significant immunodeficiency disorder * A white blood cell (WBC) count \<3×10\^9/L, and/or platelet count \<100×10\^9/L not related to hypersplenism * Diagnosis of composite α thalassemia * Participants with severe iron overload at the time of screening: severe iron overload of the liver showed by MRI, serum ferritin ≥ 5000 ng/mL, or moderate to severe iron overload of the heart * Presence of unusual antibody of red blood cell antigens or tested positive for platelet antibody * Meet the criteria for allo-HSCT and with an identified willing donor with a full HLA match * Prior receipt of gene therapy or allo-HSCT * Immediate family member (i.e. parent or siblings) with a known Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome and familial adenomatous polyposis) * Diagnosis of a significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study * History of major organ damage including: 1. Liver function test suggest AST or ALT levels \>3× upper limit of normal (ULN); 2. Total serum bilirubin value \>2.5×ULN;if combined with Gilbert syndrome, total bilirubin \>3×ULN and direct bilirubin value \>2.5×ULN; 3. History of bridging fibrosis, cirrhosis; 4. Left ventricular ejection fraction \<45%; 5. New York Heart Association (NYHA) class III or IV congestive heart failure; 6. Severe arrhythmia requiring medical treatment; 7. Uncontrolled hypertension or unstable angina pectoris; 8. Myocardial infarction or bypass or stent surgery within 12 months before drug administration; 9. Valvular disease with clinical significance; 10. Baseline calculated eGFR\<60mL/min/1.73m2; 11. Pulmonary function: FEV1/FVC\<60% and/or diffusion capacity of carbon monoxide (DLco) \<60% of prediction; 12. Evidence of clinically significant pulmonary hypertension requiring medical intervention. * Uncorrectable coagulation dysfunction or history of severe bleeding disorder * Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician * Known allergy to clinical trial drug (plerixafor or G-CSF or busulfan) or ingredient(DMSO etc.) * Participation in another clinical study with an investigational drug within 30 days of Screening or participating in another clinical study with an investigational drug * Inoculated live vaccine within 6 weeks prior to screening * Pregnancy or breastfeeding women; Subjects or their sexual partners were unable to take medically recognized effective contraceptive measures during the 27-month study period * The subjects or their parents would not comply with the study procedures outlined in the protocol * Receipt of hydroxyurea therapy within 3 months before HSCT harvest * Patients considered to be ineligible for the study by the investigator for reasons other than the above
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The number, frequency and severity of adverse events (AE) within 1 year after reinfusion of KL003 drug products | Up to 24 months post transplant | Frequency and severity of AEs & SAEs identified according to NCI CTCAE 5.0 |
| Engraftment time of neutrophil | Up to 42 days post transplant | The first day when neutrophils ≥ 0.5×10\^9/L for 3 consecutive days |
| Engraftment time of platelet | Up to 42 days post transplant | The first day of platelet count ≥ 20.0×10\^9/L for 7 consecutive days after platelet transfusion independence |
| Transplant-related mortality within 100 days and within 1 year after reinfusion of KL003 drug product | Up to 1 year post transplant | — |
| Percentage of participants with successful lentiviral vector transduced CD34+ stem cell engraftment | Up to 42 days post transplant | Successful engraftment was defined as neutrophil count \[ANC\] ≥0.5×10\^9/L for 3 consecutive days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The duration of transfusion independence | Up to 24 months post transplant | — |
| Changes in the frequency and volume of blood transfusion | Up to 24 months post transplant | — |
| The proportion of participants who meet the definition of transfusion independence (TI) for at least 6 months | Up to 24 months post transplant | TI is defined as Hb ≥ 90.0 g/L after reinfusion and without disease-related routine blood transfusion for 6 months |
Countries
China
Outcome results
None listed