A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CTX001 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
Administered by IV infusion following myeloablative conditioning with busulfan
Other Names:
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Outcome Measures
Primary Outcome Measures
- 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
- 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) [Screening visit through Month 24 visit]
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."
- 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) [Screening visit through Month 24 visit]
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.
- 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]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
- Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
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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:
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A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator's judgement.
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Prior allo-HSCT.
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Subjects with associated α-thalassemia and >1 alpha deletion or alpha multiplications.
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Subjects with sickle cell beta thalassemia variant.
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Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
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White blood cell (WBC) count <3 × 109/L or platelet count <50 × 109/L not related to hypersplenism.
Other protocol defined Inclusion/Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Stanford University | Stanford | California | United States | 94305 |
| 2 | Ann & Robert Lurie Children's Hospital of Chicago | Chicago | Illinois | United States | 60611 |
| 3 | Columbia University | Manhattan | New York | United States | 10027 |
| 4 | The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers | Nashville | Tennessee | United States | 37203 |
| 5 | Hospital for Sick Children | Toronto | Canada | ||
| 6 | BC Children's Hospital | Vancouver | Canada | ||
| 7 | University Hospital Duesseldorf | Düsseldorf | Germany | ||
| 8 | University Hospital Regensburg | Regensburg | Germany | ||
| 9 | University Hospital Tübingen | Tuebingen | Germany | ||
| 10 | Bambino Gesu | Rome | Italy | ||
| 11 | Imperial College Healthcare | London | United Kingdom | ||
| 12 | University College London Hospitals NHS Foundation Trust | London | United Kingdom |
Sponsors and Collaborators
- Vertex Pharmaceuticals Incorporated
- CRISPR Therapeutics
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CTX001-111