EDIT-301 for Autologous Hematopoietic Stem Cell Transplant (HSCT) in Participants With Transfusion-Dependent Beta Thalassemia (TDT)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of treatment with EDIT-301 in adult participants with Transfusion Dependent beta Thalassemia

Detailed Description
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This is a Phase 1/2 single-arm, open-label, multicenter study evaluating the safety, tolerability, and efficacy of a single unit dose of EDIT-301 for autologous hematopoietic stem cell transplant in adult participants with TDT, age 18 to 35 years, inclusive

Official Title
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A Multicenter Study to Evaluate the Safety, Tolerability, and Efficacy of a Single Dose of Autologous Clustered Regularly Interspaced Short Palindromic Repeats Gene-edited Cluster of Differentiation 34 (CD34+) Human Hematopoietic Stem and Progenitor Cells (HSPC) (EDIT-301) in Transfusion-Dependent Beta Thalassemia (TDT)

Conditions
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Transfusion Dependent Beta Thalassemia, Hemoglobinopathies, Thalassemia Major, Thalassemia Intermedia

Intervention / Treatment
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* Genetic: EDIT-301


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of Transfusion Dependent B-Thalassemia as defined by: Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE) based on historical data in medical records, and History of at least 100 mL/kg/year or 10 U/year of packed red blood cell (RBC) transfusions in the 2 years prior to signing informed consent Clinically stable and eligible to undergo autologous HSCT Karnofsky Performance Status ≥ 70 Key Exclusion Criteria: Available 10/10 human leukocyte antigen (HLA)-matched related donor Prior HSCT or contraindications to autologous HSCT Participants with associated a history of α-thalassemia and > 1 alpha chain deletion, or alpha multiplications as documented in medical records Participants with a history of other inherited hemoglobinopathy or thalassemic mutation (Hb S, C, D or other) as documented in medical records Prior receipt of gene therapy Inadequate bone marrow function, as defined by white blood cell count of < 3 x 10^9/L or a platelet count < 100 x 10^9/L (without hypersplenism), per investigator judgement Inadequate organ function Advanced liver disease Any prior or current malignancy, or immunodeficiency disorder, Immediate family member with a known or suspected Familial Cancer Syndrome Clinically significant and active bacterial, viral, fungal, or parasitic infection

Ages Eligible for Study
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Minimum Age: 18 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: EDIT-301<br>EDIT-301 (autologous gene edited (CD)34+ hematopoietic stem cells) will be administered as a one-time intravenous infusion. | Genetic: EDIT-301<br>* Administered by intravenous infusion after myeloablative conditioning with busulfan.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving engraftment defined as neutrophil engraftment (defined as demonstrating absolute neutrophil count (ANC) ≥ 0.5 x 10^9/L post EDIT-301 infusion for 3 consecutive measurements obtained on different days) |  | EDIT-301 infusion (Day 0) to 42 days post EDIT-301 infusion | 
| Frequency and severity of adverse events (AEs) (incidence of AEs and Grade 3 or higher serious adverse events, using National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.5.0) |  | Screening through up to 24 months post EDIT-301 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of HSPC engraftment | Time to neutrophil engraftment | EDIT-301 infusion (Day 0) to first day in which 3 consecutive measurements obtained on different days demonstrate ANC ≥ 0.5 x 10^9/L up to 24 months post EDIT-301 infusion | 
| Kinetics of HSPC engraftment | Time to platelet engraftment | EDIT-301 infusion (Day 0) to first day of 3 consecutive measurements of platelets ≥ 50 x 10^9/L for at least 1 week following the last platelet transfusion and 10 days following thrombopoietin mimetics use up to 24 months post EDIT-301 infusion. | 
| Incidence of transplant related mortality |  | EDIT-301 infusion (Day 0) through Day 100 post EDIT-301 infusion and from EDIT-301 infusion (Day 0) through 12 months post EDIT-301 infusion | 
| Incidence of all-cause mortality |  | Screening through up to 24 months post EDIT-301 infusion | 
| Proportion of alleles per participant with intended genetic modification present in peripheral blood over time |  | EDIT-301 infusion (Day 0) through up to 24 months post EDIT-301 infusion | 
| Proportion of alleles per participant with intended genetic modification present in bone marrow cells over time |  | EDIT-301 infusion (Day 0) through up to 24 months post EDIT-301 infusion | 
| Change in the fetal hemoglobin (HbF) concentration compared to baseline overtime |  | Baseline through up to 24 months post EDIT-301 infusion | 
| Change in the total hemoglobin concentration compared to baseline overtime |  | Baseline through up to 24 months post EDIT-301 infusion | 
| Proportion of participants with hemoglobin concentration ≥ 9 g/dL |  | EDIT-301 infusion (Day 0) through 3, 6, 12 months up to 24 months post EDIT-301 infusion | 
| Proportion of participants achieving the sustained transfusion reduction (TR) for at least 6 months and at least 12 months from 3 months post-EDIT-301 infusion |  | 3 months post EDIT-301 infusion through up to 24 months post EDIT-301 infusion | 
| Proportion of participants achieving the sustained transfusion independence (TI) for at least 6 months and, at least 12 months from 3 months post EDIT-301 infusion |  | 3 months through up to 24 months post EDIT-301 infusion | 
| Change in parameters of iron overload compared to baseline over time |  | Baseline through up to 24 months post EDIT-301 infusion | 
| Proportion of participants receiving iron chelation therapy over time |  | EDIT-301 infusion (Day 0) through up to 24 months post EDIT-301 infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta-Thalassemia, Hemoglobinopathies, CRISPR-Cas 12a, Autologous CD34+