A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

• ClinicalTrials.gov Identifier: NCT03852498
• Recruitment Status: Active, not recruiting
• First Posted: February 25, 2019
• Last Update Posted: April 4, 2022
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Study Description

Brief Summary:

Study ALD-104 is an international, non-randomized, open-label, multi-site study in male participants (Less than or equal to [< or =] 17 years of age at enrollment) with cerebral adrenoleukodystrophy (CALD). Approximately 35 participants will be infused with Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine.

This trial will evaluate the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, for the treatment of 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.

Condition or disease	Intervention/treatment	Phase
Cerebral Adrenoleukodystrophy (CALD)	Genetic: Lenti-D	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: January 24, 2019
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: February 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Lenti-D Drug Product; Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of > or = 5.0*10^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) following myeloablative conditioning with busulfan and fludarabine on Day 1.

Genetic: Lenti-D; Participants received a single IV infusion of Lenti-D Drug Product.; Other Names: elivaldogene autotemcel; eli-cel

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants who are Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 [ Time Frame: Month 24 post-transplant ]
   The MFDs are loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement.
2. Percentage of Participants with Neutrophil Engraftment After Drug Product Infusion [ Time Frame: 42 days post-drug product infusion ]

Secondary Outcome Measures :

1. Percentage of Participants Without Gadolinium Enhancement (GdE) at Month 24 [ Time Frame: Month 24 post-transplant ]
   Percentage of participants without Gadolinium Enhancement (that is [i.e.,] negative for Gadolinium Enhancement [GdE-]) on Magnetic Resonance Imaging (MRI).
2. Change in Total Neurologic Function Score (NFS) From Baseline to Protocol Scheduled Visits [ Time Frame: From Baseline through study completion (up to Month 24 [+or- 1 month] post-transplant) ]
   The NFS is a 25-point score used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms (functional domains) across 6 categories. Listed here are the 15 symptoms followed by their maximal score out of 25 points: a) Hearing / auditory processing problems-1, b) Aphasia / apraxia-1, c) Loss of communication-3, d) Vision impairment /field cut-1, e) Cortical blindness-2, f) Swallowing / other CNS dysfunctions-2, g) Tube feeding-2, h) Running difficulties / hyperreflexia-1, i) Walking difficulties / spasticity / spastic gait (no assistance)-1, j) Spastic gait (needs assistance)-2, k) Wheelchair dependence-2, l) Complete loss of voluntary movement-3, m) Episodes of incontinence -1, n) Total incontinence-2, o) Nonfebrile seizures-1. A score of "0" denotes absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain.
3. Major Functional Disability (MFD)-Free Survival Over Time [ Time Frame: up to Month 24 (+or- 1 month) post-transplant ]
   MFD-free survival over time is defined as time from drug product infusion to either a rescue cell administration or second transplant, MFD, or death due to any cause, whichever occurs first.
4. Overall Survival [ Time Frame: up to Month 24 (+or- 1 month) post-transplant ]
5. Detectable Vector Copy Number (VCN) in Peripheral Blood Cells by Month 6 [ Time Frame: Month 6 post-transplant ]
6. Percentage of Participants who Experience Either Acute (Greater Than or Equal to [> or =] Grade II) or Chronic Grafts Versus Host Disease (GVHD) at Month 24 [ Time Frame: Month 24 post-transplant ]
7. Time to Neutrophil Engraftment Post-drug Product Infusion [ Time Frame: 42 days post-drug product infusion ]
8. Percentage of Participants with Platelet Engraftment by Month 24 [ Time Frame: Month 24 post-drug product infusion ]
9. Time to Platelet Engraftment Post-drug Product Infusion [ Time Frame: up to Month 24 post-drug product infusion ]
10. Percentage of Participants with Loss of Neutrophil Engraftment Post-drug Product Infusion by Month 24 [ Time Frame: Month 24 post-drug product infusion ]
11. Percentage of Participants who Undergo a Subsequent Hematopoietic Stem Cell (HSC) Infusion by Month 24 [ Time Frame: Month 24 post-transplant ]
12. Percentage of Participants who Experience Transplant-Related Mortality Through 100 and 365 days Post-drug Product Infusion [ Time Frame: Through 100 and 365 days post-drug product infusion ]
13. Percentage of Participants with Adverse Events (AEs) in Selected Categories [ Time Frame: Month 24 post-transplant ]
    Percentage of participants with clinical > or = Grade 3 AEs, investigational medicinal product (IMP)-related AEs, all serious adverse events (SAEs), AEs > or = Grade 3 infections by Month 24.
14. Percentage of Participants with Potentially Clinically Significant Changes in Laboratory Parameters by Month 24 [ Time Frame: Month 24 post-transplant ]
    Laboratory parameters will include hematology, clinical chemistry, and liver function tests.
15. Percentage of Participants who Experience Greater Than or Equal to (> or =) Grade II Acute GVHD by Month 24 [ Time Frame: Month 24 post-transplant ]
16. Percentage of Participants who Experience Chronic GVHD by Month 24 [ Time Frame: Month 24 post-transplant ]
17. Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
18. Number of in-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
19. Duration of in-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
20. Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
21. Duration of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24 [ Time Frame: Month 24 post-transplant ]
22. Number of Participants in Which Vector-Derived Replication Competent Lentivirus (RCL) is Detected by Month 24 [ Time Frame: Month 24 post-transplant ]
23. Number of Participants with Insertional Oncogenesis by Month 24 [ Time Frame: Month 24 post-transplant ]
    Insertional oncogenesis including Myelodysplasia, Leukemia, Lymphoma by Month 24.

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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 cerebral ALD 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 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 HIV, hepatitis B or C virus, or human T lymphotrophic virus 1 (HTLV-1).
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 hematopoietic stem cells, 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.

Contacts and Locations

Locations

United States, California

Lucile Packard Children's Hospital

Palo Alto, California, United States, 94304

United States, Massachusetts

Boston Children's Hospital/Massachusetts General Hospital

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

France

Hôpital Robert Debré

Paris, France, 75019

Germany

Universitätsklinikum Leipzig AöR

Leipzig, Germany, 04103

Italy

Ospedale Pediatrico Bambino Gesù

Rome, Italy, 00165

Netherlands

Prinses Maxima Center

Utrecht, Netherlands, 3508AB

United Kingdom

UCL-ICH/Great Ormond Street Hospital

London, United Kingdom, WC1N3JH

Sponsors and Collaborators

bluebird bio

Investigators

• Study Director: Andrew Dietz, MD; bluebird bio, Inc.

More Information

• Responsible Party: bluebird bio
• ClinicalTrials.gov Identifier: NCT03852498
• Other Study ID Numbers: ALD-104; 2018-001145-14 ( EudraCT Number )
• First Posted: February 25, 2019
• Last Update Posted: April 4, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Bluebird bio is committed to transparency and appropriately de-identified patient-level datasets and supporting documents may be shared following attainment of applicable marketing approvals associated with this study and consistent with criteria established by bluebird bio and/or industry best practices to maintain the privacy of study participants. For enquiries, please contact us at datasharing@bluebirdbio.com.

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

Keywords provided by bluebird bio:

Adrenoleukodystrophy; X-linked adrenoleukodystrophy; Gene therapy; Hematopoietic stem cell

Additional relevant MeSH terms:

Adrenoleukodystrophy; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases