Clinical trial NCT03852498: A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
Official title: A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cerebral Adrenoleukodystrophy (CALD)
Keywords: Adrenoleukodystrophy
X-linked adrenoleukodystrophy
Gene therapy
Hematopoietic stem cell
Lead sponsor: bluebird bio
Sponsor class: INDUSTRY
First posted: 2019-02-25
Enrollment: 35
Sex: MALE
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of Lenti-D Drug Product (also known as elivaldogene autotemcel or Skysona, hereafter referred to as eli-cel) after myeloablative conditioning with busulfan and fludarabine in participants with CALD. A participant's blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the participant following myeloablative conditioning. Enrollment and treatment in Study ALD-104 have been completed and further enrollment in this study is not expected, although participants follow-up remains ongoing in the long-term follow-up Study LTF-304 (NCT02698579).


Eligibility criteria: Inclusion Criteria:

1. Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local Institutional Review Board (IRB)/independent ethics committee (IEC) approved consent. Informed assent will be sought from capable participants, in accordance with the directive of the IRB/IEC and with local requirements.
2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.
3. Active CALD as defined by:

   1. Elevated very long chain fatty acids (VLCFA) values, and
   2. Active central nervous system (CNS) disease established by central radiographic review of brain MRI demonstrating: i) Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and ii) Gadolinium enhancement (GdE) on MRI of demyelinating lesions.
4. NFS \< or = 1.

Exclusion Criteria:

1. Prior receipt of an allogeneic transplant or gene therapy.
2. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels. Note: participants must discontinue use of these medications at time of consent.
3. Receipt of an investigational study drug or procedure within 3 months before Screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study.
4. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).
5. Hematological compromise as evidenced by:

   1. Peripheral blood absolute neutrophil count (ANC) count \<1500 cells/ cubic millimeter (mm\^3), and either
   2. Platelet count \<100,000 cells/mm\^3, or
   3. Hemoglobin \<10 gram per deciliter (g/dL).
6. Hepatic compromise as evidenced by:

   1. Aspartate transaminase (AST) value greater than (\>) 2.5 × upper limit of normal (ULN)
   2. Alanine transaminase (ALT) value \>2.5 × ULN
   3. Total bilirubin value \>3.0 milligram per deciliter (mg/dL), except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable
7. Baseline estimated glomerular filtration rate \<70 milliliter per minute (mL/min)/1.73 square meter (m\^2).
8. Cardiac compromise as evidenced by left ventricular ejection fraction \<40 percent (%).
9. Immediate family member with a known or suspected Familial Cancer Syndrome.
10. Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection.
11. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B virus (HBV); hepatitis C virus (HCV); human T lymphotrophic virus 1 (HTLV-1). (Note that participants who have been vaccinated against HBV \[positive for HBV surface antibodies\] who are negative for other markers of prior HBV infection \[e.g., negative for HBV core Ab\] are eligible. Participants with past exposure to HBV \[hepatitis B core antibody \[HBcAb\] -positive and/or hepatitis B e-antigen antibody \[HBeAb\]-positive\] are also eligible for the study provided they have a negative test for HBV DNA. Also note that participants who are positive for anti-hepatitis C Ab are eligible as long as they have a negative hepatitis C viral load).
12. Any clinically significant cardiovascular, hematological, or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.
13. Absence of adequate contraception for fertile participants.
14. Any contraindications to the use of Granulocyte colony-stimulating factor (G-CSF) or plerixafor during the mobilization of HSCs, and any contraindications to the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations.
15. Known hypersensitivity to protamine sulfate.

Primary outcomes:
measure: Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24
timeFrame: At Month 24
measure: Percentage of Participants Who Achieved Neutrophil Engraftment After Drug Product Infusion
timeFrame: By 42 days post-drug infusion
Secondary outcomes:
measure: Percentage of Participants Without Gadolinium Enhancement (i.e. GdE-) on Magnetic Resonance Imaging (MRI) at Month 24
timeFrame: At Month 24
measure: Number of Participants With Change in Neurologic Function Score (NFS) From Baseline to Month 24
timeFrame: Baseline up to Month 24
measure: Number of Participants Who Achieved Stable NFS at Month 24
timeFrame: At Month 24
measure: Major Functional Disability (MFD)-Free Survival Rate
timeFrame: At 24 months after Lenti-D drug infusion
measure: Overall Survival Rate
timeFrame: At 24 months after Lenti-D drug infusion
measure: Median Detectable Vector Copy Number (VCN) in Peripheral Blood Cells by Month 6
timeFrame: By Month 6 post-transplant
measure: Time to Neutrophil Engraftment (NE) After Drug Product Infusion
timeFrame: By 42 days post-drug infusion
measure: Percentage of Participants With Platelet Engraftment by Month 24
timeFrame: By Month 24
measure: Time to Platelet Engraftment Post-drug Product Infusion
timeFrame: By Month 24
measure: Percentage of Participants With Loss of Neutrophil Engraftment Post-drug Product Infusion by Month 24
timeFrame: By Month 24
measure: Percentage of Participants Who Underwent a Subsequent Allo- Hematopoietic Stem Cell Transplantation (HSCT) Infusion by Month 24
timeFrame: By Month 24
measure: Percentage of Participants Who Experienced Either Acute (>= Grade 2) or Chronic Graft Versus Host Disease (GVHD) at Month 24
timeFrame: At Month 24
measure: Percentage of Participants Who Experienced >= Grade 2 Acute Graft Versus Host Disease (GVHD) by Month 24
timeFrame: By Month 24
measure: Percentage of Participants Who Experienced Chronic GVHD by Month 24
timeFrame: By Month 24
measure: Percentage of Participants Who Experienced Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion
timeFrame: From time of drug product infusion through 100 and 365 days post-drug product infusion
measure: Percentage of Participants With Clinical >= Grade 3 Adverse Events (AEs), All Investigational Medicinal Product-related AEs, All Serious Adverse Events (SAEs), and >= Grade 3 Infections
timeFrame: From date of informed consent up to Month 24
measure: Number of Participants With >= Grade 3 Prolonged Cytopenia on or After Rel Day 60 And Rel Day 100
timeFrame: Prolonged cytopenias occurring on or after Rel Day 60 and Rel Day 100 following drug product infusion
measure: Percentage of Participants With Potentially Clinically Significant Changes in Laboratory Parameters by Month 24
timeFrame: From Day 1 to Month 24
measure: Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24
timeFrame: From Post-Neutrophil Engraftment up to Month 24
measure: Median Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24
timeFrame: From Post-Neutrophil Engraftment up to Month 24
measure: Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24
timeFrame: From Post-Neutrophil Engraftment up to Month 24
measure: Median Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24
timeFrame: From post-neutrophil engraftment up to Month 24
measure: Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24
timeFrame: From post-neutrophil engraftment up to Month 24
measure: Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24
timeFrame: From post-neutrophil engraftment up to Month 24
measure: Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24
timeFrame: From post-neutrophil engraftment up to Month 24
measure: Number of Participants Who Tested Positive and Negative for Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24
timeFrame: By Month 24
measure: Number of Participants With Insertional Oncogenesis by Month 24
timeFrame: By Month 24 post-transplant
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
city: Boston
country: United States
facility: Boston Children's Hospital/Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Paris
country: France
facility: Hôpital Robert Debré
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Utrecht
country: Netherlands
facility: Prinses Maxima Center
city: London
country: United Kingdom
facility: UCL-ICH/Great Ormond Street Hospital
Study officials:
affiliation: bluebird bio, Inc.
name: Himal Lal Thakar, MD
role: STUDY_DIRECTOR
References: