Gene Transfer for Patients With Sickle Cell Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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Gene Transfer for Patients With Sickle Cell Disease Using a Gamma Globin Lentivirus Vector: An Open Label Phase 1/2 Pilot Study

Conditions
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Anemia, Sickle Cell

Intervention / Treatment
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* Genetic: ARU-1801


Participation Criteria
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Eligibility Criteria
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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: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Gamma Globin Lentivirus Vector
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARU-1801<br>Autologous CD34+ hematopoietic stem cells transduced ex-vivo with gamma-globin lentiviral vector. Administered via IV infusion. | Genetic: ARU-1801<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease, sickle cell anemia, hemoglobinopathies, hematopoietic stem cell, gene transfer, gene therapy