ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia

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

Tracking Information

• First Submitted Date: March 26, 2024
• First Posted Date: April 15, 2024
• Last Update Posted Date: April 15, 2024
• Estimated Study Start Date: May 1, 2024
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2024)

• Neutrophil Engraftment [ Time Frame: within 42 days after infusion ]
  time to neutrophil engraftment
• Platelet Engraftment [ Time Frame: through end of treatment, an average 1 year ]
  time to platelet engraftment
• Overall Survival at 2 years [ Time Frame: 2 years after treatment ends ]
  Survival status after treatment ends
• 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
• 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)
• 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.
• Insertional Oncogenesis [ Time Frame: through the end of the study, up to 24 months ]
  The number of subjects with insertional oncogenesis
• Clonal Predominance [ Time Frame: through the end of the study, up to 24 months ]
  The number of subjects with clonal predominance
• 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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia
• 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
• 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.

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 Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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

• Condition: Beta-Thalassemia

Intervention

Biological: ALS20

novel lentiviral vector ALS20

Study Arms

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.

Intervention: Biological: ALS20

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 11, 2024): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2027
• Estimated Primary Completion Date: December 31, 2027 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 35 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Janet Kwiatkowski, MD; 215-590-5286; kwiatkowski@chop.edu

Contact: Jaladhikumar Patel; 267-426-5602; patelj23@chop.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT06364774
• Other Study ID Numbers: 22-020309
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Children's Hospital of Philadelphia
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Hospital of Philadelphia
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Janet Kwiatkowski, MD; Children's Hospital of Philadelphia

• PRS Account: Children's Hospital of Philadelphia
• Verification Date: April 2024