Evaluation the Safety and Efficacy of KL003 Cell Injection in the Treatment of Transfusion-dependent β-thalassemia.

Study Overview
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Brief Summary
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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 β-thalassemia major.

Detailed Description
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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.

Official Title
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Evaluation the Safety and Efficacy of KL003 Cell Injection in the Treatment of Transfusion-dependent β-thalassemia.

Conditions
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Transfusion-dependent Beta-Thalassemia

Intervention / Treatment
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* Genetic: KL003 cell injection Drug Product


Participation Criteria
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Eligibility Criteria
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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: Liver function test suggest AST or ALT levels >3× upper limit of normal (ULN); Total serum bilirubin value >2.5×ULN;if combined with Gilbert syndrome, total bilirubin >3×ULN and direct bilirubin value >2.5×ULN; History of bridging fibrosis, cirrhosis; Left ventricular ejection fraction <45%; New York Heart Association (NYHA) class III or IV congestive heart failure; Severe arrhythmia requiring medical treatment; Uncontrolled hypertension or unstable angina pectoris; Myocardial infarction or bypass or stent surgery within 12 months before drug administration; Valvular disease with clinical significance; Baseline calculated eGFR<60mL/min/1.73m2; Pulmonary function: FEV1/FVC<60% and/or diffusion capacity of carbon monoxide (DLco) <60% of prediction; 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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KL003 cell injection Drug Product<br>Each recruited subject will accept KL003 Transplantation. | Genetic: KL003 cell injection Drug Product<br>* Transplant of auto-HSC transduced with lentiviral vector encoding βA-T87Q-globin gene.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with successful lentiviral vector transduced CD34+ stem cell engraftment | Successful engraftment was defined as neutrophil count [ANC] ≥0.5×10^9/L for 3 consecutive days | Up to 42 days post transplant | 
| Engraftment time of neutrophil | The first day when neutrophils ≥ 0.5×10^9/L for 3 consecutive days | Up to 42 days post transplant | 
| Engraftment time of platelet | The first day of platelet count ≥ 20.0×10^9/L for 7 consecutive days after platelet transfusion independence | Up to 42 days post transplant | 
| Transplant-related mortality within 100 days and within 1 year after reinfusion of KL003 drug product |  | Up to 1 year post transplant | 
| The number, frequency and severity of adverse events (AE) within 1 year after reinfusion of KL003 drug products | Frequency and severity of AEs & SAEs identified according to NCI CTCAE 5.0 | Up to 24 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants who meet the definition of transfusion independence (TI) for at least 6 months | TI is defined as Hb ≥ 90.0 g/L after reinfusion and without disease-related routine blood transfusion for 6 months | Up to 24 months post transplant | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta-Thalassaemia, Hematopoietic Stem-Cell Transplantation