Transfusion Dependent Beta-thalassemia
Conditions
Keywords
Beta thalassemia, Beta-thalassemia, Thalassemia major, Cooley's anemia, ZFN mediated genome editing, zinc finger nuclease
Brief summary
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
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
Interventions
GENETICST-400 Investigational product
Single dose of ST-400 following chemotherapy conditioning with busulfan
Sponsors
Sangamo Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Informed Consent 2. Clinical diagnosis of TDT with ≥ 8 documented RBC transfusion events per year on an annualized basis in the 2-years prior to screening 3. Confirmed beta-thalassemia diagnosis by molecular genetic testing 4. Clinically stable and eligible to receive conditioning chemotherapy 5. 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
1. Previous history of autologous or allogeneic blood stem cell transplantation or solid organ transplantation 2. Pregnant or breastfeeding female 3. Medical contraindication to mobilization, apheresis, or conditioning 4. Significant liver, lung, heart, or kidney dysfunction 5. Diagnosis of HIV or evidence of active HBV or HCV 6. History of significant bleeding disorder or uncontrolled seizures 7. 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. 8. Currently participating in another clinical trial using an investigational study medication, or recent participation in such a trial 9. Previous treatment with gene therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Baseline, Weeks 26, 52, and 156 after ST-400 infusion | Change from baseline clinical laboratory measurement of Hb fractions (A and F in g/dL) \[Time Frame: Up to 156 weeks after ST-400 infusion\] |
| Clinical Laboratory Measurements of Percent (%) HbF | Baseline, Weeks 26, 52, and 156 after ST-400 infusion | Change from baseline percent (%) HbF \[Time Frame: Up to 156 weeks after ST-400 infusion\] |
| Annualized Frequency of Packed RBC Transfusions | 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) | 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 |
| Annualized Volume (mL) of Packed RBC Transfusions | 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) | Historical baseline defined as transfusion support in the 2 years prior to screening. |
Countries
United States
Participant flow
Recruitment details
The original enrollment goal was six subjects were to be enrolled in the Phase 1/2 study ST-400-01, but 5 subjects were enrolled and dosed. One subject from the 5 dosed withdrew consent prior to completing the study. Subjects who received treatment with ST-400 were asked to participate in a separate observational long-term safety study.
Participants by arm
| Arm | Count |
|---|---|
| ST-400 Investigational Product 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
ST-400 Investigational product: Single dose of ST-400 following chemotherapy conditioning with busulfan | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow Up (Weeks 52-156 Post Infusion) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | ST-400 Investigational Product |
|---|---|
| Age, Continuous | 28.4 years STANDARD_DEVIATION 7.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hemoglobin A (g/dL) at Baseline | 11.040 g/dL STANDARD_DEVIATION 0.6006 |
| Hemoglobin F (g/dL) at Baseline | 0.169 g/dL STANDARD_DEVIATION 0.0835 |
| Hemoglobin F Percentage at Baseline | 1.48 Percentage STANDARD_DEVIATION 0.76 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Sex Female | 2 Participants |
| Sex: Female, Male Sex Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 3 / 5 |
Outcome results
Primary
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
Time frame: Up to 156 weeks after the ST-400 infusion
Population: All subjects who received the ST-400 infusion
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ST-400 Investigational Product | Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 156 Weeks After the ST-400 Infusion | Incidence of non-serious adverse events | 5 participants |
| ST-400 Investigational Product | Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 156 Weeks After the ST-400 Infusion | Incidence of serious adverse events | 2 participants |
Secondary
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
Time frame: 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)
Population: Annualized Frequency of Blood Product Transfusion in Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ST-400 Investigational Product | Annualized Frequency of Packed RBC Transfusions | Baseline transfusion support 2 years prior to screening/consent | 17.393 PRBC transfusions/year | Standard Deviation 5.435 |
| ST-400 Investigational Product | Annualized Frequency of Packed RBC Transfusions | At ST-400 Infusion (Day 0) | 21.518 PRBC transfusions/year | Standard Deviation 4.8806 |
| ST-400 Investigational Product | Annualized Frequency of Packed RBC Transfusions | After hematopoietic reconstitution (up to 156 weeks after ST-400 infusion) | 19.665 PRBC transfusions/year | Standard Deviation 5.6716 |
Secondary
Annualized Volume (mL) of Packed RBC Transfusions
Historical baseline defined as transfusion support in the 2 years prior to screening.
Time frame: 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)
Population: Blood Product Annualized Total Volume Transfused in Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ST-400 Investigational Product | Annualized Volume (mL) of Packed RBC Transfusions | Baseline transfusion support 2 years prior to screening/consent | 10295.984 mL/year | Standard Deviation 4063.3661 |
| ST-400 Investigational Product | Annualized Volume (mL) of Packed RBC Transfusions | At ST-400 infusion (Day 0) | 7453.191 mL/year | Standard Deviation 4204.3456 |
| ST-400 Investigational Product | Annualized Volume (mL) of Packed RBC Transfusions | After hematopoietic reconstitution (up to 156 weeks after ST-400 infusion) | 7068.788 mL/year | Standard Deviation 4480.8901 |
Secondary
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) \[Time Frame: Up to 156 weeks after ST-400 infusion\]
Time frame: Baseline, Weeks 26, 52, and 156 after ST-400 infusion
Population: Hb fractions (A and F in g/dL) Change from Baseline to Week 26, Week 52 and Week 156 in Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin A (g/dL) Change from Baseline to Week 26 | -3.648 g/dL | Standard Deviation 2.0401 |
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin A (g/dL) Change from Baseline to Week 52 | -3.227 g/dL | Standard Deviation 2.0789 |
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin A (g/dL) Change from Baseline to Week 156 | -0.281 g/dL | Standard Deviation 1.5834 |
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin F (g/dL) Change from Baseline to Week 26 | 1.025 g/dL | Standard Deviation 1.0898 |
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin F (g/dL) Change from Baseline to Week 52 | 0.405 g/dL | Standard Deviation 0.2851 |
| ST-400 Investigational Product | Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL) | Hemoglobin F (g/dL) Change from Baseline to Week 156 | 0.502 g/dL | Standard Deviation 0.2936 |
Secondary
Clinical Laboratory Measurements of Percent (%) HbF
Change from baseline percent (%) HbF \[Time Frame: Up to 156 weeks after ST-400 infusion\]
Time frame: Baseline, Weeks 26, 52, and 156 after ST-400 infusion
Population: Change Percent (%) HbF from Baseline to Week 26, Week 52 and Week 156 in Safety Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ST-400 Investigational Product | Clinical Laboratory Measurements of Percent (%) HbF | Week 26 | 12.83 Percentage of Hemoglobin F | Standard Deviation 14.282 |
| ST-400 Investigational Product | Clinical Laboratory Measurements of Percent (%) HbF | Week 52 | 5.30 Percentage of Hemoglobin F | Standard Deviation 3.188 |
| ST-400 Investigational Product | Clinical Laboratory Measurements of Percent (%) HbF | Week 156 | 4.35 Percentage of Hemoglobin F | Standard Deviation 3.04 |