Evaluation of Safety and Efficacy of CTX001 in Pediatric Participants With Transfusion-Dependent β-Thalassemia (TDT)

Study Overview
=================
Brief Summary
-----------------
This is a single-dose, open-label study in pediatric participants with TDT. The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) (CTX001).

Official Title
-----------------
A Phase 3 Study to Evaluate the Safety and Efficacy of a Single Dose of CTX001 in Pediatric Subjects With Transfusion-Dependent β-Thalassemia

Conditions
-----------------
Beta-Thalassemia, Thalassemia, Genetic Diseases, Inborn, Hematologic Diseases, Hemoglobinopathies

Intervention / Treatment
-----------------
* Biological: CTX001


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis of TDT as defined by: Documented homozygous or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Participants can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning History of at least 100 mL/kilograms (kg)/year of packed RBC transfusions in the prior 24 months before signing of consent (or the last rescreening for patients going through repeat screening) or, for participants initiating transfusion therapy <24 months before signing of consent, requirement for packed RBC transfusion at least every 3 to 4 weeks for ≥6 months Eligible for autologous stem cell transplant as per investigator's judgment. Key Exclusion Criteria: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement Prior hematopoietic stem cell transplant (HSCT) Participants with associated α-thalassemia and >1 alpha deletion, or alpha multiplications Participants with sickle cell β-thalassemia variant Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CTX001<br>CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive single infusion of CTX001 through central venous catheter. | Biological: CTX001<br>* Administered by intravenous infusion following myeloablative conditioning with busulfan.<br>* Other names: Exa-cel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants who Achieve Transfusion Independence for at Least 12 Consecutive Months (TI12) |  | Up to 24 Months After CTX001 Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From Signing of Informed Consent up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Engraftment (First day of 3 Consecutive Measurements of Absolute Neutrophil Count [ANC] ≥500 per Microliter [mcgL] on 3 Different Days) |  | Within 42 Days After CTX001 Infusion | 
| Time to Engraftment |  | Up to 24 Months After CTX001 Infusion | 
| Incidence of Transplant-related Mortality (TRM) Within 100 Days After CTX001 Infusion |  | Within 100 Days After CTX001 Infusion | 
| Incidence of TRM Within 12 Months After CTX001 Infusion |  | Within 12 Months After Infusion | 
| Incidence of All-cause Mortality |  | From Signing of Informed Consent up to 24 Months After CTX001 Infusion | 
| Proportion of Participants who Achieve Transfusion Independence for at Least 6 Consecutive Months (TI6) |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants Achieving at Least 95 Percent (%), 90%, 85%, 75% and 50% Reduction in Annualized Transfusions |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Relative Reduction in Annualized Volume of RBC Transfusions |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Transfusion Free Duration for Participants who Achieve TI12 |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in Peripheral Blood Over Time |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in CD34+ Cells of the Bone Marrow Over Time |  | Up to 24 Months After CTX001 Infusion | 
| Change in Fetal Hemoglobin Concentration Over Time |  | From Baseline (Pre-transfusion) up to 24 Months After CTX001 Infusion | 
| Change in Total Hemoglobin Concentration Over Time |  | From Baseline (Pre-transfusion) up to 24 Months After CTX001 Infusion |