CSL200 Gene Therapy in Adults With Severe Sickle Cell Disease

Study Overview
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Brief Summary
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This is a phase 1 pilot study of CSL200 in adult subjects with severe sickle cell disease. The primary objectives of this study are to evaluate the safety of the following: collection of CD34+ hematopoietic stem / progenitor cells by apheresis after mobilization with plerixafor, reduced intensity conditioning with melphalan, and administration of CSL200.

Official Title
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A Phase 1 Pilot Study to Evaluate the Safety and Feasibility of Gene Therapy With CSL200 (Autologous Enriched CD34+ Cell Fraction That Contains CD34+ Cells Transduced With Lentiviral Vector Encoding Human γ-GlobinG16D and Short-Hairpin RNA734) in Adult Subjects With Severe Sickle Cell Disease

Conditions
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Anemia, Sickle Cell

Intervention / Treatment
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* Biological: Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of sickle cell disease with the homozygous HbS homozygous genotype (HbSS) or an HbSβ thalassemia variant (ie, HbSβ0 thalassemia or HbSβ+ thalassemia) genotype, confirmed by hemoglobin studies. Fetal hemoglobin (HbF) ≤ 15%. Severe sickle cell disease symptomatology, defined as any one or more of the following: ≥ 2 episodes of acute chest syndrome in the last 2 years. ≥ 3 episodes of severe pain events requiring a visit to a medical facility and treatment with opioids in the last 2 years. > 2 episodes of recurrent priapism in the last 2 years. Red-cell alloimmunization (> 2 antibodies) during long-term transfusion therapy (lifetime history). Chronic transfusions for primary or secondary prophylaxis (lifetime history). Trans-thoracic echocardiograph evidence of tricuspid valve regurgitant jet velocity ≥ 2.7 m/sec (lifetime history). Clinically significant neurologic event (eg, ischemic stroke) or any neurological deficit lasting > 24 hours. Not eligible for human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation, defined as follows: no medically eligible, available, and willing 10/10 matched HLA-identical sibling donor, unless subject has declined this treatment option (as documented in the informed consent form). Not eligible for, declined, or, as judged by the investigator, failed therapy with hydroxyurea and if still on hydroxyurea is able to interrupt hydroxyurea starting at the beginning of the transfusions, before mobilization and apheresis. Exclusion Criteria: Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency. Thiopurine S-methyltransferase (TPMT) deficiency. Alpha thalassemia. Inadequate bone marrow function, defined as at least 1 of the following: Absolute neutrophil count < 1000/µL. Platelet count < 120,000/µL.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: CSL200<br>Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734 | Biological: Autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734<br>* Cryopreserved formulated autologous enriched CD34+ cell fraction that contains CD34+ cells transduced with lentiviral vector encoding human γ-globinG16D and short-hairpin RNA734 in a bag for infusion Plerixafor to mobilize hematopoietic stem cells prior to each apheresis Single dose melphalan before administration of CSL200<br>* Other names: CSL200;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) associated with the administration of CSL200 | Adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is medically significant. Adverse event of special interest (AESI) is defined in this study as any of the following: acute immune reactions, autoimmunity to CSL200; malignancy; predominant integration site in presence of malignancy or other abnormality. | Up to 48 weeks | 
| Number of subjects experiencing AEs, SAEs, and AESIs associated with the administration of CSL200 |  | Up to 48 weeks | 
| Number of AEs, SAEs, and AESIs associated with the collection of CD34+ HSPCs by apheresis after mobilization with plerixafor |  | Up to 6 weeks | 
| Number of subjects experiencing AEs, SAEs, and AESIs associated with the collection of CD34+ HSPCs by apheresis after mobilization with plerixafor |  | Up to 6 weeks | 
| Number of AEs, SAEs, and AESIs associated with reduced intensity conditioning with melphalan |  | Up to 3 weeks | 
| Number of subjects experiencing AEs, SAEs, and AESIs associated with reduced intensity conditioning with melphalan |  | Up to 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total by-subject number of CD34+ HSPCs collected in total and in each apheresis session | Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by CD34+ HSPCs collected | Up to 2 days | 
| Number of subjects receiving plerixafor and number of plerixafor doses administered by subject | Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by plerixafor administrations | Up to 2 days | 
| Number of subjects undergoing apheresis and number of apheresis sessions by subject | Collection of CD34+ HSPCs by apheresis after mobilization with plerixafor assessed by apheresis sessions | Up to 2 days | 
| The number of subjects undergoing reduced intensity conditioning with melphalan and able to receive CSL200 | Reduced intensity conditioning assessed by subjects receiving melphalan | 2 days | 
| Number of subjects receiving CSL200 |  | 1 day | 
| By-subject number of separate CSL200 drug products administered |  | 1 day | 
| Number of CSL200 CD34+ HSPCs/kg administered by subject and by CSL200 drug product |  | 1 day | 
| By-subject total number and percentage of CD34+ HSPCs transduced with CAL-H |  | Up to 48 weeks | 
| Vector copy number (VCN) | VCN will be determined by using the average number of CAL-H vector genomes per cell | Up to 48 weeks |