A Study to Assess the Safety, Tolerability, and Efficacy of ST-400 for Treatment of Transfusion-Dependent Beta-thalassemia (TDT)

Study Overview
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Brief Summary
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This is a single-arm, multi-site, single-dose, Phase 1/2 study to assess ST-400 in 6 subjects with transfusion-dependent β-thalassemia (TDT) who are ≥18 and ≤40 years of age. ST-400 is a type of investigational therapy that consists of gene edited cells. ST-400 is composed of the patient's own blood stem cells which are genetically modified in the laboratory using Sangamo's zinc finger nuclease (ZFN) technology to disrupt a precise and specific sequence of the enhancer of the BCL11A gene (which normally suppresses fetal hemoglobin production in erythrocytes). This process is intended to boost fetal hemoglobin (HbF), which can substitute for reduced or absent adult (defective) hemoglobin. ST-400 is then infused back into the patient after receiving conditioning chemotherapy to make room for the new cells in the bone marrow, with the aim of producing new erythrocytes with increased amounts of HbF. The primary objective is to understand safety and tolerability of ST-400, and secondary objectives are to assess the effects on HbF levels and transfusion requirements.

Detailed Description
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Once consented, study participants will progress through the following stages: Screening: in-person visit at the study site to confirm eligibility for proceeding Collection: autologous (self) blood stem cells are harvested at the study site, also known as apheresis Manufacturing of ST-400: no study participant activities expected Infusion: conditioning chemotherapy, followed by infusion of ST-400, occurs at the study site Follow-up: follow up at the study site to monitor for safety and effectiveness of the study

Official Title
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A Phase 1/2, Open-label, Single-arm Study to Assess the Safety, Tolerability, and Efficacy of ST-400 Autologous Hematopoietic Stem Cell Transplant for Treatment of Transfusion-Dependent Beta-thalassemia (TDT)

Conditions
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Transfusion Dependent Beta-thalassemia

Intervention / Treatment
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* Genetic: ST-400 Investigational product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent Clinical diagnosis of TDT with ≥ 8 documented RBC transfusion events per year on an annualized basis in the 2-years prior to screening Confirmed beta-thalassemia diagnosis by molecular genetic testing Clinically stable and eligible to receive conditioning chemotherapy Able and willing to use an effective method of contraception from the signing of the informed consent and for one year following ST-400 infusion. Exclusion Criteria: Previous history of autologous or allogeneic blood stem cell transplantation or solid organ transplantation Pregnant or breastfeeding female Medical contraindication to mobilization, apheresis, or conditioning Significant liver, lung, heart, or kidney dysfunction Diagnosis of HIV or evidence of active HBV or HCV History of significant bleeding disorder or uncontrolled seizures History of active malignancy in past 5 years (non-melanoma skin cancer or cervical cancer in situ permitted) any history of hematologic malignancy, or family history of cancer predisposition syndrome without negative testing result in the study candidate. Currently participating in another clinical trial using an investigational study medication, or recent participation in such a trial Previous treatment with gene therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: ST-400 Investigational product<br>ST-400 Investigational product is composed of autologous CD34+ hematopoietic stem/progenitor cells that are genetically modified ex vivo at the erythroid-specific enhancer of the BCL11A gene | Genetic: ST-400 Investigational product<br>* Single dose of ST-400 following chemotherapy conditioning with busulfan<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 156 Weeks After the ST-400 Infusion | Safety and tolerability assessed by number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 156 weeks after the ST-400 infusion | Up to 156 weeks after the ST-400 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Change from baseline clinical laboratory measurement of Hb fractions (A and F in g/dL) [Time Frame: Up to 156 weeks after ST-400 infusion] | Baseline, Weeks 26, 52, and 156 after ST-400 infusion | 
| Clinical Laboratory Measurements of Percent (%) HbF | Change from baseline percent (%) HbF [Time Frame: Up to 156 weeks after ST-400 infusion] | Baseline, Weeks 26, 52, and 156 after ST-400 infusion | 
| Annualized Frequency of Packed RBC Transfusions | Calculation of annualized frequency and volume of packed red blood cell (PRBC) transfusions after ST-400 infusion transfusion support in the 2 years prior to screening | From Baseline (2 years prior to screening/consent), to ST-400 Infusion (Day 0), after hematopoietic reconstitution and up to 156 weeks (post ST-400 infusion) | 
| Annualized Volume (mL) of Packed RBC Transfusions | Historical baseline defined as transfusion support in the 2 years prior to screening. | From Baseline (2 years prior to screening/consent), to ST-400 Infusion (Day 0), after hematopoietic reconstitution and up to 156 weeks (post ST-400 infusion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Beta thalassemia, Beta-thalassemia, Thalassemia major, Cooley's anemia, ZFN mediated genome editing, zinc finger nuclease