A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia

Study Overview
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Brief Summary
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This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects with transfusion-dependent β-thalassemia (TDT). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.

Official Title
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A Phase 1/2/3 Study of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects With Transfusion-Dependent β-Thalassemia

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

Intervention / Treatment
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* Biological: CTX001


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by: Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Subjects 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/kg/year or ≥10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening. 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 allo-HSCT. Subjects with associated α-thalassemia and >1 alpha deletion or alpha multiplications. Subjects with sickle cell beta thalassemia variant. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator. White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism. Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 12 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: CTX001<br>CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Subjects will receive a single infusion of CTX001 through a central venous catheter. | Biological: CTX001<br>* Administered by IV infusion following myeloablative conditioning with busulfan<br>* Other names: Exa-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving transfusion independence for at least 12 consecutive months (TI12) |  | From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion] | 
| Proportion of subjects with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days) |  | Within 42 days after CTX001 infusion | 
| Time to neutrophil and platelet engraftment |  | Days post-infusion to engraftment | 
| Frequency and severity of collected adverse events (AEs) |  | Signing of informed consent through Month 24 visit | 
| Incidence of transplant-related mortality (TRM) |  | Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion | 
| All-cause mortality |  | Signing of informed consent through Month 24 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving transfusion independence for at least 6 consecutive months (TI6) |  | From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion | 
| Proportion of subjects achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized transfusions 60 days after CTX001 infusion |  | From Day 60 up to 24 months post-CTX001 infusion | 
| Relative change from baseline in transfusions 60 days after CTX001 infusion |  | From Day 60 up to 24 months post-CTX001 infusion | 
| Duration of transfusion free in subjects who have achieved TI12 |  | From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion | 
| Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time |  | Day 1 CTX001 infusion through Month 24 visit | 
| Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time |  | Day 1 CTX001 infusion through Month 24 visit | 
| Change in fetal hemoglobin concentration over time |  | Baseline (pre-transfusion) through Month 24 visit | 
| Change in total hemoglobin concentration over time |  | Baseline (pre-transfusion) through Month 24 visit | 
| Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L) | The EQ-5D-5L Questionnaire consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 5 levels: no problems to extreme problems. The subject marks the most appropriate statement in each dimension, resulting in a 1-digit number for that dimension. The digits can be combined in a 5-digit number describing the subject's health state. The EQ VAS records the subject's self-rated health on a 100-point VAS, endpoints labelled the best health you can imagine and the worst health you can imagine. | Screening visit through Month 24 visit | 
| Change in health-related quality of life (HRQoL) from baseline over time using the Functional assessment of cancer therapy-bone marrow transplant questionnaire (FACT-BMT) | The FACT-BMT Questionnaire includes physical, social, family, emotional, and functional well-being, and treatment specific concerns of bone marrow transplantation. Each statement has a 5-point Likert-type response scale ranging from 0=not at all to 4=very much. The subject marks one number per line as it applies to the past 7 days. Questionnaires are scored; the higher the score, the better the QOL. | Screening visit through Month 24 visit | 
| Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y) |  | Screening visit through Month 24 visit | 
| Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) |  | Screening visit through Month 24 visit | 
| Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload |  | Screening visit through Month 24 visit | 
| Proportion of subjects receiving iron chelation therapy |  | 1 month post-CTX001 infusion through Month 24 visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRISPR-Cas9, Beta-Thalassemia, Hemoglobinopathies