Gene Transfer for Patients With Sickle Cell Disease

NCT02186418 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: ARU-1801_Ph1_01
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this Phase 1/2 study is to determine the feasibility and safety of stem cell collection and gamma-globin gene transfer, and success of gene correction in subjects with sickle cell disease

Conditions

Anemia, Sickle Cell

Keywords

sickle cell disease; sickle cell anemia; hemoglobinopathies; hematopoietic stem cell; gene transfer; gene therapy

Outcome Measures

Primary Outcomes (14)

• Incidence of Grade 3 allergic reaction

  Incidence of Grade 3 allergic reaction associated with infusion of transduced cell product

  From infusion (Day 0) to 15 years

• Incidence of Grade 4 infection

  Incidence of Grade 4 infection following infusion of transduced cell product uncontrolled for ≥14 days

  From infusion (Day 0) to 15 years

• Incidence of Grade 4 neutropenia

  Incidence of Grade 4 neutropenia lasting \>1 month following melphalan

  From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells

• Incidence of Grade 3 or 4 organ toxicity

  Incidence of Grade 3 or 4 organ toxicity attributable to study procedures

  From screening to 15 years post-infusion of transduced cells

• Incidence of Adverse Events (AEs)

  From screening to 15 years post-infusion of transduced cells

• Incidence of Serious Adverse Events (SAEs)

  From screening to 15 years post-infusion of transduced cells

• Incidence of death due to study procedures

  From screening to 15 years post-infusion of transduced cells

• Incidence of hematological malignancy

  Incidence of hematological malignancy due to vector insertion

  From infusion (Day 0) to 15 years

• Incidence of hematological cancer

  Incidence of hematological cancer related to investigational product or study medications/procedures

  From screening to 15 years post-infusion of transduced cells

• Time to neutrophil recovery

  Number of days from melphalan-induced nadir to the first of 3 consecutive absolute neutrophil counts ≥500 cells/µL

  From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells

• Time to platelet recovery

  Number of days from melphalan-induced nadir to the first of 3 consecutive platelet counts \>50,000 cells/µL and independent of platelet transfusion for ≥7 days consecutive days.

  From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells

• ≥8x10⁶kg viable CD34+ cells

  Number of subjects with a total number of CD34+ cells recovered from all collections combined (mobilized peripheral blood and bone marrow) of at least ≥8x10⁶kg viable CD34+ cells

  Up to Year 2

• ≥4x10⁶ CD34+ cells/kg body weight transduced

  Proportion of subjects for which a minimum of 4x10⁵ CD34+ cells/kg body weight from all collections combined have been successfully transduced

  Up to Year 2

• Bone marrow aspirates with ≥1% gene-marked cells

  Number of subjects with bone marrow aspirates at 1-year post-infusion with ≥1% gene-marked cells

  Infusion (Day 0) to 1 year

Secondary Outcomes (10)

• Quantity of Hb (hemoglobin) subtypes

  Months 6, 12, 18, 24 and year 3, 4, 5

• Change in proportion of antisickling/sickling hemoglobin

  Baseline to Month 6 through 12

• Percentage of F-RBC (fetal hemoglobin content in red blood cells)

  Months 6, 12, 18, 24, 36

• Percentage of F-retics (fetal hemoglobin content in reticulocytes)

  Months 6, 12, 18, 24, 36

• Presence of vector copies in white blood cell fraction

  Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24

Study Arms (1)

ARU-1801

EXPERIMENTAL

Autologous CD34+ hematopoietic stem cells transduced ex-vivo with gamma-globin lentiviral vector. Administered via IV infusion.

Genetic: ARU-1801

Interventions

ARU-1801 GENETIC

Autologous CD34+ hematopoietic stem cells transduced ex-vivo with a gamma-globin lentiviral vector * Subjects with sickle cell anemia will undergo hematopoietic stem cell procurement by bone marrow harvest or apheresis after mobilization with plerixafor * Reduced intensity chemotherapy conditioning with single dose melphalan will be used to facilitate engraftment of ex-vivo transduced cells.

ARU-1801

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent form.
• Has confirmed diagnosis of sickle cell disease (SCD)
• Has severe sickle cell disease, defined as one or more of the following:
• Minimum of two episodes of clinically diagnosed acute chest syndrome (ACS) requiring hospital admission, or one life threatening episode of ACS requiring intensive care unit (ICU) admission for exchange transfusion and/or intubation, or frequent ACS episodes which necessitate treatment with chronic transfusion therapy.
• Frequent painful vaso-occlusive episodes (VOEs) which significantly interfere with normal life activities, defined as a history of 2 or more severe acute sickle pain events per year requiring additional treatment at a medical facility outside of home pain management over the preceding 2-year period prior to study enrollment, or that necessitate chronic transfusion therapy.
• Subjects on chronic transfusion therapy for severe disease symptoms other than those listed above, and which interfere with normal life activities.
• Has failed hydroxyurea therapy, was unable to tolerate hydroxyurea therapy, or has actively made the choice to not take the recommended daily hydroxyurea advised for severe disease (Note: must be off hydroxyurea therapy for 2 months prior to stem cell collection). If refusing hydroxyurea, the subject must document that they have been educated about the benefits and continue to refuse the treatment. Patients placed on chronic transfusion therapy instead of hydroxyurea for severe disease are eligible. Subjects unable to take hydroxyurea due to financial or safety monitoring constraints are eligible.
• Has adequate functional status and organ function as determined at Screening.

You may not qualify if:

• Female subjects who are pregnant or lactating/breastfeeding.
• Female subjects who are not surgically sterile, postmenopausal or who refuse to practice effective method of birth control as determined by the Investigator for one year after receiving the study drug. Women must also agree not to breastfeed for 1 year after receiving the study drug.
• Any participant of reproductive potential who refuses to agree to use an appropriate contraceptive method determined by the Investigator, for 1 year after receiving the study drug.
• Patients with an active malignant disease or receiving treatment for any type of cancer (except squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin).
• Current diagnosis or history of hepatitis B, hepatitis C, or HIV.
• Has received another study drug within 30 days, or 5 half-lives of the last dose (whichever is longer), prior to screening.
• Has severe obstruction, restriction or diffusion defect on pulmonary function tests.
• Has uncontrolled bacterial, viral or fungal infections within 1 month prior to starting the conditioning part of the study. Subjects with fever should wait for symptoms to resolve before starting the conditioning part of the study.
• Has a history of stroke or is at moderate to high risk of primary stroke (eg receiving chronic transfusions or hydroxyurea for primary prevention of stroke; has severe cerebral vasculopathy defined as moderate stenosis in \>2 arterial segments; and/or has sever stenosis/occlusion in ≤2 segments in the polygon of Willis or presence of Moyamoya-like disease).
• Patients with alpha thalassemia sickle cell disease.
• Has previous liver biopsy showing cirrhosis, bridging hepatic fibrosis, or active hepatitis; or has received chronic transfusions and has previous evidence of iron overload and evidence of liver fibrosis by noninvasive liver imaging.
• Has a matched sibling donor, unless the subject has declined this option or this option is not feasible. Documentation must be included as part of the informed consent process for subjects who decline this option.
• Has a known hypersensitivity to any study treatments (e.g. melphalan, plerixafor).

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead

Study Sites (1)

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Publications (1)

• Grimley M, Davies SM, Shrestha A, Shova A, Asnani M, Kent M, Sayani F, Quinn CT, Niss O, Lutzko C, Mehta PA, Khandelwal P, Little C, Chandra S, Felker S, Chi M, Kalfa TA, Knight-Madden J, Arumugam PI, Ramos KN, Witting S, Latham T, Bushman FD, Malik P. Lentiviral gene therapy with reduced-intensity conditioning for sickle cell disease: a phase 1/2 trial. Nat Med. 2025 Jul;31(7):2204-2212. doi: 10.1038/s41591-025-03662-2. Epub 2025 May 26.

  PMID: 40419809 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; Hemoglobinopathies

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Stella M. Davies, MB BS, PhD, MRCP

  Children's Hospital Medical Center, Cincinnati

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Gamma Globin Lentivirus Vector

Study Record Dates

• First Submitted: June 30, 2014
• First Posted: July 10, 2014
• Study Start: July 1, 2014
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2022
• Last Updated: April 12, 2024

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)