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
Overview
- Phase
- Phase 2
- Intervention
- CTX001
- Conditions
- Beta-Thalassemia
- Sponsor
- Vertex Pharmaceuticals Incorporated
- Enrollment
- 59
- Locations
- 14
- Primary Endpoint
- Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participans 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.
Investigators
Eligibility Criteria
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). 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/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
Exclusion Criteria
- •A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator's judgement
- •Prior allo-HSCT
- •Participants with associated α-thalassemia and \>1 alpha deletion or alpha multiplications
- •Participants 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.
Arms & Interventions
CTX001
CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive a single infusion of CTX001 through a central venous catheter.
Intervention: CTX001
Outcomes
Primary Outcomes
Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)
Time Frame: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]
Incidence of transplant-related mortality (TRM)
Time Frame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
Proportion of participants with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
Time Frame: Within 42 days after CTX001 infusion
Time to neutrophil and platelet engraftment
Time Frame: Days post-infusion to engraftment
Frequency and severity of collected adverse events (AEs)
Time Frame: Signing of informed consent through Month 24 visit
All-cause mortality
Time Frame: Signing of informed consent through Month 24 visit
Secondary Outcomes
- Proportion of participants 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 participants achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion(From Month 10 up to 24 months post-CTX001 infusion)
- Relative reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion(From Month 10 up to 24 months post-CTX001 infusion)
- Duration of transfusion free in participants 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)
- 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)
- 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 participants receiving iron chelation therapy(1 month post-CTX001 infusion through Month 24 visit)