A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

Study Description

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Brief Summary:

This trial will assess the efficacy and safety of autologous CD34+ hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, for the treatment of cerebral adrenoleukodystrophy (CALD). A subject'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 subject following myeloablative conditioning.

Condition or disease	Intervention/treatment	Phase
Cerebral Adrenoleukodystrophy (CALD)	Genetic: Lenti-D Drug Product	Phase 2; Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
Study Start Date :	August 2013
Estimated Primary Completion Date :	July 2020
Estimated Study Completion Date :	December 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Lenti-D Drug Product	Genetic: Lenti-D Drug Product; Lenti-D Drug Product (autologous CD34+ cell-enriched population that contains cells transduced with Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein, suspended in a cryopreservative solution) is administered intravenously. Lenti-D Drug Product is administered by IV infusion following myeloablative conditioning with busulfan and cyclophosphamide.

Outcome Measures

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Primary Outcome Measures :

1. Proportion of subjects who are alive and have none of the 6 major functional disabilities (MFDs) at Month 24 (i.e. Month 24 MFD-free survival). [ Time Frame: 24 months (±1 months) post-transplant ]

   MFDs are:

   • loss of communication
   • cortical blindness
   • tube feeding
   • total incontinence
   • wheelchair dependence
   • complete loss of voluntary movement
2. The proportion of subjects who experience either acute (≥Grade II) or chronic graft versus host disease (GVHD) at Month 24. [ Time Frame: 24 months (±1 months) post-transplant ]

Secondary Outcome Measures :

1. Incidence of resolution of gadolinium positivity on MRI (i.e., GdE-). [ Time Frame: 24 months (±1 months) post-transplant ]
2. Time to sustained resolution of gadolinium positivity on MRI (i.e., GdE-). [ Time Frame: 24 months (±1 months) post-transplant ]
   Sustained is defined as gadolinium resolution without a subsequent evaluation indicating gadolinium positivity.
3. Change in total NFS from Baseline to Month 24. [ Time Frame: 24 months (±1 months) post-transplant ]
4. MFD-free survival over time [ Time Frame: 24 months (±1 months) post-transplant ]
5. Overall survival [ Time Frame: 24 months (±1 months) post-transplant ]

Eligibility Criteria

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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 IRB/Independent Ethics Committee (IEC) approved consent (informed assent will be sought from capable subjects, 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, subject assent.

3. Active cerebral ALD as defined by:

   1. Elevated VLCFA values, and
   2. Active CNS disease established by central radiographic review of brain magnetic resonance imaging (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. Neurologic Function Score (NFS) ≤ 1.

Exclusion Criteria:

1. Receipt of an allogeneic transplant or gene therapy.
2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes).
3. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels. Note: subjects must discontinue use of these medications at time of consent.
4. 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.
5. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).

6. Hematological compromise as evidenced by:

   • Peripheral blood ANC count < 1500 cells/mm3,
   • Platelet count < 100,000 cells/mm3, or
   • Hemoglobin < 10 g/dL.
   • Uncorrected bleeding disorder.

7. Hepatic compromise as evidenced by:

   • Aspartate transaminase (AST) value > 2.5×ULN
   • Alanine transaminase (ALT) value > 2.5×ULN
   • Total bilirubin value > 3.0 mg/dL, except if there is a diagnosis of Gilbert's Syndrome and the subject is otherwise stable
8. Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 mL/min)
9. Cardiac compromise as evidenced by left ventricular ejection fraction <40%
10. Immediate family member with a known or suspected familial cancer syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).
11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection
12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B; hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that subjects who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core antibody (Ab)] are eligible. Subjects with past exposure to HBV [HBcAb positive and/or HBeAb positive] are also eligible for the study provided they have a negative test for HBV DNA. Also note that subjects who are positive for anti-hepatitis C antibody are eligible as long as they have a negative hepatitis C viral load).
13. Any clinically significant cardiovascular or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.
14. Absence of adequate contraception for fertile subjects. Male subjects and their female partners are required to use two different effective methods of contraception from Screening through at least 6 months after drug product infusion.

Contacts and Locations

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Locations

United States, California
Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center
Los Angeles, California, United States, 90095
United States, Massachusetts
Boston Children's Hospital/Massachusetts General Hospital
Boston, Massachusetts, United States, 02115
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
France
Hôpital Bicêtre
Le Kremlin-Bicêtre Cedex, France, 94275
United Kingdom
Great Ormond Street Hospital for Children NHS Foundation Trust
London, United Kingdom, WC1N3JH

Sponsors and Collaborators

bluebird bio

Investigators

Study Director:	Elizabeth McNeil, MD.	bluebird bio, Inc.
Principal Investigator:	David Williams, MD	Boston Children’s Hospital
Principal Investigator:	Christine Duncan, MD	Boston Children’s Hospital
Principal Investigator:	Florian Eichler, MD	Massachusetts General Hospital
Principal Investigator:	Satiro de Oliveira, MD	University of California, Los Angeles
Principal Investigator:	Paul Orchard, MD	University of Minnesota - Clinical and Translational Science Institute
Principal Investigator:	Adrian Thrasher, MD, PhD	Great Ormond Street Hospital for Chidren NHS Foundation Trust
Principal Investigator:	Patrick Aubourg, MD, PhD	Hôpital Bicêtre

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638. doi: 10.1056/NEJMoa1700554. Epub 2017 Oct 4.

Responsible Party:	bluebird bio
ClinicalTrials.gov Identifier:	NCT01896102 History of Changes
Other Study ID Numbers:	ALD-102
First Posted:	July 11, 2013
Last Update Posted:	May 16, 2018
Last Verified:	May 2018

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