Gene Transfer for Patients With Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT02186418
• Recruitment Status: Active, not recruiting
• First Posted: July 10, 2014
• Last Update Posted: November 17, 2022
• Sponsor: Children's Hospital Medical Center, Cincinnati
• Information provided by (Responsible Party): Children's Hospital Medical Center, Cincinnati

Study Description

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

Condition or disease	Intervention/treatment	Phase
Anemia, Sickle Cell	Genetic: ARU-1801	Phase 1; Phase 2

Detailed Description:

This study will assess the feasibility, safety and efficacy of gene transfer using ARU-1801 (CD34+ cells transduced with the gamma-globin lentiviral vector). Gene transfer will occur ex-vivo into CD34+ enriched human bone marrow or plerixafor-mobilized peripheral blood hematopoietic stem cells (HSC) collected from subjects with severe sickle cell disease (SCD). Subjects will undergo reduced intensity chemotherapy conditioning with single-dose melphalan to facilitate engraftment of ex-vivo ARU-1801 via IV infusion. Subjects will return to the study site at regular intervals for follow-up for 2 years after the ARU-1801 infusion. It is anticipated that a separate long-term follow-up (LTFU) clinical study will be initiated, in which all subjects completing the 2 year study visit will be asked to consent and enroll, and will followed for a further 13 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Gamma Globin Lentivirus Vector
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Gene Transfer for Patients With Sickle Cell Disease Using a Gamma Globin Lentivirus Vector: An Open Label Phase 1/2 Pilot Study
• Actual Study Start Date: July 2014
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2035

Arms and Interventions

Arm

Intervention/treatment

Experimental: ARU-1801; Autologous CD34+ hematopoietic stem cells transduced ex-vivo with gamma-globin lentiviral vector. Administered via IV infusion.

Genetic: ARU-1801; 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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Grade 3 allergic reaction [ Time Frame: From infusion (Day 0) to 15 years ]
   Incidence of Grade 3 allergic reaction associated with infusion of transduced cell product
2. Incidence of Grade 4 infection [ Time Frame: From infusion (Day 0) to 15 years ]
   Incidence of Grade 4 infection following infusion of transduced cell product uncontrolled for ≥14 days
3. Incidence of Grade 4 neutropenia [ Time Frame: From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells ]
   Incidence of Grade 4 neutropenia lasting >1 month following melphalan
4. Incidence of Grade 3 or 4 organ toxicity [ Time Frame: From screening to 15 years post-infusion of transduced cells ]
   Incidence of Grade 3 or 4 organ toxicity attributable to study procedures
5. Incidence of Adverse Events (AEs) [ Time Frame: From screening to 15 years post-infusion of transduced cells ]
6. Incidence of Serious Adverse Events (SAEs) [ Time Frame: From screening to 15 years post-infusion of transduced cells ]
7. Incidence of death due to study procedures [ Time Frame: From screening to 15 years post-infusion of transduced cells ]
8. Incidence of hematological malignancy [ Time Frame: From infusion (Day 0) to 15 years ]
   Incidence of hematological malignancy due to vector insertion
9. Incidence of hematological cancer [ Time Frame: From screening to 15 years post-infusion of transduced cells ]
   Incidence of hematological cancer related to investigational product or study medications/procedures
10. Time to neutrophil recovery [ Time Frame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells ]
    Number of days from melphalan-induced nadir to the first of 3 consecutive absolute neutrophil counts ≥500 cells/µL
11. Time to platelet recovery [ Time Frame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells ]
    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.
12. ≥8x10⁶kg viable CD34+ cells [ Time Frame: Up to Year 2 ]
    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
13. ≥4x10⁶ CD34+ cells/kg body weight transduced [ Time Frame: Up to Year 2 ]
    Proportion of subjects for which a minimum of 4x10⁵ CD34+ cells/kg body weight from all collections combined have been successfully transduced
14. Bone marrow aspirates with ≥1% gene-marked cells [ Time Frame: Infusion (Day 0) to 1 year ]
    Number of subjects with bone marrow aspirates at 1-year post-infusion with ≥1% gene-marked cells

Secondary Outcome Measures :

1. Quantity of Hb (hemoglobin) subtypes [ Time Frame: Months 6, 12, 18, 24 and year 3, 4, 5 ]
   Quantification of HbF^G16D and other Hb subtypes, including HbF (endogenous), HbS, adult Hb (HbA), HbA2 and, if applicable, HbC and HbE
2. Change in proportion of antisickling/sickling hemoglobin [ Time Frame: Baseline to Month 6 through 12 ]
   Change in the proportion of antisickling/sickling hemoglobin ([HbF+HbF^G16D+HbA2]/HbS) in months 6-12 post-transplantation compared to baseline
3. Percentage of F-RBC (fetal hemoglobin content in red blood cells) [ Time Frame: Months 6, 12, 18, 24, 36 ]
   Measured by flow cytometry
4. Percentage of F-retics (fetal hemoglobin content in reticulocytes) [ Time Frame: Months 6, 12, 18, 24, 36 ]
   Measured by flow cytometry
5. Presence of vector copies in white blood cell fraction [ Time Frame: Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24 ]
6. Presence of vector copies in bone marrow [ Time Frame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36 ]
   Measured by qPCR and DNA
7. Presence of gene-marked colony-forming unit cells (CFU-c) in bone marrow (BM) indicting gene transfer [ Time Frame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36 ]
   Measured by CFU-c assay by qPCR on individual CFU-c
8. Number of annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant [ Time Frame: Baseline to year 15 ]
   Change in disease severity
9. Frequency of opioid use pre-transplant versus post-transplant [ Time Frame: Baseline to year 15 ]
   Change in disease severity
10. Change in QoL (Quality of Life) [ Time Frame: Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5 ]
    Measured by adult sickle cell quality of life measurement (ASCQ-Me®)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

• 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:

  1. 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.
  2. 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.
  3. 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.

Exclusion Criteria

• 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).

Other protocol-defined inclusion-exclusion criteria may apply.

Contacts and Locations

Locations

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Sponsors and Collaborators

Children's Hospital Medical Center, Cincinnati

Investigators

• Study Chair: Stella M. Davies, MB BS, PhD, MRCP; Children's Hospital Medical Center, Cincinnati

More Information

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT02186418
• Other Study ID Numbers: ARU-1801_Ph1_01
• First Posted: July 10, 2014
• Last Update Posted: November 17, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Children's Hospital Medical Center, Cincinnati:

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

Additional relevant MeSH terms:

Anemia, Sickle Cell; Anemia; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Genetic Diseases, Inborn