Gene Transfer for Patients With Sickle Cell Disease
- Conditions
- Anemia, Sickle Cell
- Interventions
- Genetic: ARU-1801
- Registration Number
- NCT02186418
- Lead Sponsor
- Children's Hospital Medical Center, Cincinnati
- 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
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 7
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description ARU-1801 ARU-1801 Autologous CD34+ hematopoietic stem cells transduced ex-vivo with gamma-globin lentiviral vector. Administered via IV infusion.
- Primary Outcome Measures
Name Time Method Incidence of Grade 4 infection From infusion (Day 0) to 15 years Incidence of Grade 4 infection following infusion of transduced cell product uncontrolled for ≥14 days
Incidence of Grade 4 neutropenia From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells Incidence of Grade 4 neutropenia lasting \>1 month following melphalan
Incidence of Grade 3 or 4 organ toxicity From screening to 15 years post-infusion of transduced cells Incidence of Grade 3 or 4 organ toxicity attributable to study procedures
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 ≥8x10⁶kg viable CD34+ cells 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
Incidence of Grade 3 allergic reaction From infusion (Day 0) to 15 years Incidence of Grade 3 allergic reaction associated with infusion of transduced cell product
Time to neutrophil recovery 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
Time to platelet recovery 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.
Incidence of Adverse Events (AEs) From screening to 15 years post-infusion of transduced cells Incidence of hematological malignancy From infusion (Day 0) to 15 years Incidence of hematological malignancy due to vector insertion
Incidence of hematological cancer From screening to 15 years post-infusion of transduced cells Incidence of hematological cancer related to investigational product or study medications/procedures
≥4x10⁶ CD34+ cells/kg body weight transduced 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
Bone marrow aspirates with ≥1% gene-marked cells 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
Name Time Method Quantity of Hb (hemoglobin) subtypes 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
Presence of vector copies in white blood cell fraction Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24 Change in proportion of antisickling/sickling hemoglobin 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
Percentage of F-retics (fetal hemoglobin content in reticulocytes) Months 6, 12, 18, 24, 36 Measured by flow cytometry
Presence of gene-marked colony-forming unit cells (CFU-c) in bone marrow (BM) indicting gene transfer Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36 Measured by CFU-c assay by qPCR on individual CFU-c
Number of annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant Baseline to year 15 Change in disease severity
Percentage of F-RBC (fetal hemoglobin content in red blood cells) Months 6, 12, 18, 24, 36 Measured by flow cytometry
Frequency of opioid use pre-transplant versus post-transplant Baseline to year 15 Change in disease severity
Change in QoL (Quality of Life) Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5 Measured by adult sickle cell quality of life measurement (ASCQ-Me®)
Presence of vector copies in bone marrow Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36 Measured by qPCR and DNA
Trial Locations
- Locations (1)
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States