Clinical trial NCT03432364: A Study to Assess the Safety, Tolerability, and Efficacy of ST-400 for Treatment of Transfusion-Dependent Beta-thalassemia (TDT)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Transfusion Dependent Beta-thalassemia
Keywords: Beta thalassemia
Beta-thalassemia
Thalassemia major
Cooley's anemia
ZFN mediated genome editing
zinc finger nuclease
Lead sponsor: Sangamo Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-02-14
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) up to 156 Weeks After the ST-400 Infusion
timeFrame: Up to 156 weeks after the ST-400 infusion
Secondary outcomes:
measure: Clinical Laboratory Measurement of Hemoglobin (Hb) Fractions (A and F in g/dL)
timeFrame: Baseline, Weeks 26, 52, and 156 after ST-400 infusion
measure: Clinical Laboratory Measurements of Percent (%) HbF
timeFrame: Baseline, Weeks 26, 52, and 156 after ST-400 infusion
measure: Annualized Frequency of Packed RBC Transfusions
timeFrame: 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)
measure: Annualized Volume (mL) of Packed RBC Transfusions
timeFrame: 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)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Boston
country: United States
facility: Dana-Farber Boston Children's Cancer and Blood Disorders Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Sangamo Therapeutics, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.