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ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia

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ClinicalTrials.gov Identifier: NCT06364774
Recruitment Status : Not yet recruiting
First Posted : April 15, 2024
Last Update Posted : April 15, 2024
Sponsor:
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Study Description
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Brief Summary:
The main goal of this study is to find out if the blood disorder called transfusion-dependent beta thalassemia can be safely treated by modifying blood stem cells. This is done by collecting blood stem cells from the subject, modifying those cells, adding a healthy beta globin gene, and then giving them back to the subject. It is hoped that these modified cells will decrease the need for blood transfusions. The gene modified blood stem cells are called CHOP-ALS20 ("study drug"). This experimental gene therapy has not been tried on human beings before and is not FDA approved.

Condition or disease Intervention/treatment Phase
Beta-Thalassemia Biological: ALS20 Phase 1 Phase 2

Detailed Description:

Beta thalassemia major is a hereditary blood disorder that requires lifelong regular transfusions and is associated with significant morbidity, early mortality, and decreased quality of life. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited availability of suitable donors as well as risks of graft versus host disease limit its applicability. Gene addition of a functional beta globin gene may be an alternative treatment option.

The primary objective is to assess the safety of treatment with autologous hematopoietic stem cells transduced with a novel lentiviral vector (ALS20) in subjects 18 to 35 years old with transfusion dependent beta thalassemia.

The secondary objective is to evaluate the efficacy of treatment with autologous hematopoietic stem cells transduced with a novel lentiviral vector (ALS20) in subjects 18 to 35 years old with transfusion dependent beta thalassemia.

Study Design: This is a single arm pilot, phase 1/2 study of up to 12 subjects ages 18 to 35 years who have transfusion-dependent beta thalassemia (genotypes β0β0, β+β0, β+β+, βEβ0, βEβ+, dominant β thalassemia). The study will evaluate the safety and efficacy of infusing autologous hematopoietic stem and progenitor cells (HSPC) transduced with the novel lentiviral vector ALS20 that encodes the human βA-T87Q-globin, following myeloablative conditioning with busulfan.

The main risks of this study involve risks of the genetic modification of the stem cells and the busulfan chemotherapy conditioning. Genetic modification of blood stem cells may increase the risk of blood cancer. The main risks of busulfan conditioning include prolonged low blood counts, liver injury, infertility, and cancer. There also is a risk of failure of the modified blood stem cells to grow.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single arm pilot, phase I/II study of 12 subjects.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study Evaluating the Safety and Efficacy of Gene Therapy Employing Lentiviral Vector ALS20-transduced Hematopoietic Progenitor Cells in Subjects With Transfusion-dependent-thalassemia
Estimated Study Start Date : May 1, 2024
Estimated Primary Completion Date : December 31, 2027
Estimated Study Completion Date : December 31, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: beta thalassemia
This arm will evaluate the safety and efficacy of infusing autologous hematopoietic stem and progenitor cells (HSPC) transduced with the novel lentiviral vector ALS20 that encodes the human βA-T87Q-globin gene, following myeloablative conditioning with busulfan.
 Biological: ALS20
novel lentiviral vector ALS20


Outcome Measures
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Primary Outcome Measures :
  1. Neutrophil Engraftment [ Time Frame: within 42 days after infusion ]
    time to neutrophil engraftment

  2. Platelet Engraftment [ Time Frame: through end of treatment, an average 1 year ]
    time to platelet engraftment

  3. Overall Survival at 2 years [ Time Frame: 2 years after treatment ends ]
    Survival status after treatment ends

  4. Incidence of transplant related mortality [ Time Frame: 1 year after infusion ]
    Incidence of transplant related mortality within 100 days and within 1 year after infusion

  5. Incidence of Graft Versus Host Disease [ Time Frame: through end of treatment, an average of 1 year ]
    any clinical evidence of graft versus host disease (GVHD)

  6. Incidence of Vector-Derived Replication Competent Lentivirus [ Time Frame: through end of treatment, an average of 1 year ]
    The detection of vector-derived replication competent lentivirus in any subject throughout the study until end of treatment.

  7. Insertional Oncogenesis [ Time Frame: through the end of the study, up to 24 months ]
    The number of subjects with insertional oncogenesis

  8. Clonal Predominance [ Time Frame: through the end of the study, up to 24 months ]
    The number of subjects with clonal predominance

  9. maintain total hemoglobin level of 9.0 g/dL or higher [ Time Frame: through the end of the study, up to 24 months ]
    The proportion of subjects able to discontinue regular red cell transfusions and maintain total hemoglobin level of 9.0 g/dL or higher (average over 1-year period) in the absence of red cell transfusion(transfusion independence). Success is defined as a minimum of 4 to 6 subjects achieving this endpoint.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 to 35 years at the time of consent
  2. Diagnosis of transfusion dependent beta thalassemia (β0 β0, β+β0, β+β+, βEβ0, βEβ+). Transfusion-dependent is defined as a history of receiving at least 120 mL/kg/year packed red blood cells or at least 8 transfusions per year in the past two years. The first 2 subjects enrolled must have a non- β0 β0 genotype.
  3. Genetic confirmation of α and β thalassemia diagnosis (β0β0, β+β0, β+β+, βEβ0, Eβ+ dominant β-thalassemia) by a CLIA laboratory is required.
  4. Clinically stable, Karnofsky score 70, and eligible to undergo Hematopoietic Stem Cell Transplantation (HSCT).
  5. Female subjects of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 6 months after CHOP-ALS20 infusion
  6. Male subjects of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after CHOP-ALS20 infusion

Exclusion Criteria:

  1. Prior receipt of HSCT or gene therapy
  2. An available Human Leukocyte Antigen (HLA)-matched family donor
  3. More than one alpha globin gene deletions/mutations.
  4. Any prior or current malignancy (excluding adequately treated basal or squamous cell carcinoma of the skin)
  5. Known cancer predisposition syndrome
  6. Positive for HIV-1, HIV-2, Human T Cell Lymphotropic Virus-1,2 (HTLV-1, HTLV-2) or active hepatitis B or active hepatitis C infection
  7. Clinically significant active bacterial, viral (including COVID-19 and influenza), fungal, or parasitic infection (temporary exclusion)
  8. Clinically significant bleeding disorder
  9. Evidence of cardiac dysfunction (left ventricular ejection fraction <50% or shortening fraction <27%) or clinically significant arrhythmia
  10. Evidence of advanced liver disease (ALT >5x the upper limit of normal (ULN), prothrombin time >1.5 x ULN, direct bilirubin > 3x ULN) not attributable to iron chelation therapy, or evidence of bridging fibrosis on liver biopsy or fibrosis stage of F3 or higher by magnetic resonance elastography (MRE) if obtained as part of clinical care
  11. Liver R2 or R2 MRI or liver biopsy with liver iron concentration 15 mg/g dw (temporary exclusion)
  12. Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for Hb)
  13. Pulse oximetry in room air <92%
  14. Evidence of renal dysfunction (creatinine >1.5x ULN or Glomerular Filtration Rate (GFR) <70 ml/min/1.73 m2 based on cystatin C/creatinine equation)
  15. Cardiac T2 MRI < 10 ms
  16. Platelet count <100,000/mcL or absolute neutrophil count <1000/mcL except if attributed to benign ethnic neutropenia
  17. Unable to receive red cell transfusion (significant allo/auto immunization)
  18. Uncontrolled systemic hypertension
  19. Uncontrolled seizure disorder
  20. Diagnosis of a significant psychiatric disorder that could seriously impede the ability to participate in the study
  21. Immediate family member with a known or suspected Familial Cancer Syndrome
  22. Contraindication to anesthesia
  23. For female subjects, pregnancy or breastfeeding
  24. Participation in another clinical trial of an investigational drug within 30 days or 5 drug half-lives, whichever is longer, of screening (temporary exclusion)
  25. Any other condition that would render the subject ineligible for mobilization/apheresis and/or HSCT as determined by the investigator
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06364774


Contacts
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Contact: Janet Kwiatkowski, MD 215-590-5286 kwiatkowski@chop.edu
Contact: Jaladhikumar Patel 267-426-5602 patelj23@chop.edu

Locations
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United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Contact: Janet Kwiatkowski, MD    215-590-5286    kwiatkowski@chop.edu   
Contact: Jaladhikumar Patel    267-426-5602    patelj23@chop.edu   
Principal Investigator: Janet Kwiatkowski, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Investigators
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Principal Investigator: Janet Kwiatkowski, MD Children's Hospital of Philadelphia
More Information
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Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT06364774    
Other Study ID Numbers: 22-020309
First Posted: April 15, 2024    Key Record Dates
Last Update Posted: April 15, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Children's Hospital of Philadelphia:
Thalassemia
Beta Thalassemia
gene therapy
beta globin gene
Additional relevant MeSH terms:
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Thalassemia
beta-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
 Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn