Clinical trial NCT02186418: Gene Transfer for Patients With Sickle Cell Disease
Official title: Gene Transfer For Patients With Sickle Cell Disease Using A Gamma Globin Lentivirus Vector: An Open-Label Phase 1 / 2 Pilot Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Anemia, Sickle Cell
Keywords: sickle cell disease
sickle cell anemia
hemoglobinopathies
hematopoietic stem cell
gene transfer
gene therapy
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
First posted: 2014-07-10
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Gamma Globin Lentivirus Vector
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility 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.

Primary outcomes:
measure: Incidence of Grade 3 allergic reaction
timeFrame: From infusion (Day 0) to 15 years
measure: Incidence of Grade 4 infection
timeFrame: From infusion (Day 0) to 15 years
measure: Incidence of Grade 4 neutropenia
timeFrame: From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells
measure: Incidence of Grade 3 or 4 organ toxicity
timeFrame: From screening to 15 years post-infusion of transduced cells
measure: Incidence of Adverse Events (AEs)
timeFrame: From screening to 15 years post-infusion of transduced cells
measure: Incidence of Serious Adverse Events (SAEs)
timeFrame: From screening to 15 years post-infusion of transduced cells
measure: Incidence of death due to study procedures
timeFrame: From screening to 15 years post-infusion of transduced cells
measure: Incidence of hematological malignancy
timeFrame: From infusion (Day 0) to 15 years
measure: Incidence of hematological cancer
timeFrame: From screening to 15 years post-infusion of transduced cells
measure: Time to neutrophil recovery
timeFrame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
measure: Time to platelet recovery
timeFrame: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
measure: ≥8x10⁶kg viable CD34+ cells
timeFrame: Up to Year 2
measure: ≥4x10⁶ CD34+ cells/kg body weight transduced
timeFrame: Up to Year 2
measure: Bone marrow aspirates with ≥1% gene-marked cells
timeFrame: Infusion (Day 0) to 1 year
Secondary outcomes:
measure: Quantity of Hb (hemoglobin) subtypes
timeFrame: Months 6, 12, 18, 24 and year 3, 4, 5
measure: Change in proportion of antisickling/sickling hemoglobin
timeFrame: Baseline to Month 6 through 12
measure: Percentage of F-RBC (fetal hemoglobin content in red blood cells)
timeFrame: Months 6, 12, 18, 24, 36
measure: Percentage of F-retics (fetal hemoglobin content in reticulocytes)
timeFrame: Months 6, 12, 18, 24, 36
measure: Presence of vector copies in white blood cell fraction
timeFrame: Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24
measure: Presence of vector copies in bone marrow
timeFrame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
measure: Presence of gene-marked colony-forming unit cells (CFU-c) in bone marrow (BM) indicting gene transfer
timeFrame: Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36
measure: Number of annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant
timeFrame: Baseline to year 15
measure: Frequency of opioid use pre-transplant versus post-transplant
timeFrame: Baseline to year 15
measure: Change in QoL (Quality of Life)
timeFrame: Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Stella M. Davies, MB BS, PhD, MRCP
role: STUDY_CHAIR
References: