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

NCT ID: NCT01896102

Last Updated: 2022-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-21
• Study Completion Date: 2021-03-26

Brief Summary

This trial assessed the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector (also called elivaldogene autotemcel or eli-cel), for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells were 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 were transplanted back into the participant following myeloablative conditioning. Participants in this study will be continuously followed in study LTF-304.

Detailed Description

For study ALD-102 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) were identical.

Conditions

Cerebral Adrenoleukodystrophy (CALD)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lenti-D Drug Product

Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of greater than or equal to (\>=) 5.0 × 10\^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contained cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0.

Group Type: EXPERIMENTAL

Lenti-D Drug Product (eli-cel)

Intervention Type: GENETIC

Participants received a single IV infusion of Lenti-D Drug Product.

Interventions

Lenti-D Drug Product (eli-cel)

Participants received a single IV infusion of Lenti-D Drug Product.

Intervention Type: GENETIC

Other Intervention Names

elivaldogene autotemcel; eli-cel

Eligibility Criteria

Inclusion Criteria

1. Informed consent was 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 adrenoleukodystrophy (ALD) as defined by:

1. Elevated very long chain fatty acids (VLCFA) values, and

2. Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating:

3. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and

4. Gadolinium enhancement on MRI of demyelinating lesions.

4. NFS less than or equal to (<or=) 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 very long chain fatty acids (VLCFA) levels. Note: participants 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 absolute neutrophil count (ANC) count < 1500 cells/ cubic milli meter (mm3),
• Platelet count < 100,000 cells/mm3, or
• Hemoglobin < 10 gram per deciliter (g/dL).
• Uncorrected bleeding disorder.

7. Hepatic compromise as evidenced by:

• Aspartate transaminase (AST) value > 2.5×upper limit of normal (ULN)
• Alanine transaminase (ALT) value > 2.5×ULN
• 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

8. Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 milliliter per minute [mL/min])

9. Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%)

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 participants 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. Participants with past exposure to hepatitis B virus (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 participants 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 participants. Male participants 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. If subjects are truly sexually abstinent (where true sexual abstinence is defined as being in line with the preferred and usual lifestyle of the subject), no second method is required.

15. Any contraindications to the use of granulocyte colony stimulating (G-CSF) during the mobilization of HSCs, and any contraindications to the use of busulfan or cyclophosphamide, including known hypersensitivity to the active substances or to any of the excipients in their formulations.

• Maximum Eligible Age: 17 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Genetix Biotherapeutics Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jakob Sieker, MD.

Role: STUDY_DIRECTOR

bluebird bio, Inc.

David Williams, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Christine Duncan, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Florian Eichler, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Satiro de Oliveira, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Paul Orchard, MD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Adrian Thrasher, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Great Ormond Street Hospital for Chidren NHS Foundation Trust

Patrick Aubourg, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hôpital Bicêtre

Jorn-Sven Kuhl, MD

Role: PRINCIPAL_INVESTIGATOR

University of Leipzig

Nicholas Smith, MD

Role: PRINCIPAL_INVESTIGATOR

Women and Children's Hospital

Hernan Amartino, MD

Role: PRINCIPAL_INVESTIGATOR

Medeos SRL

Locations

Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center

Los Angeles, California, United States

Boston Children's Hospital/Massachusetts General Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Medeos SRL

Buenos Aires, , Argentina

Women and Children's Hospital

North Adelaide, South Australia, Australia

Hôpital Bicêtre

Le Kremlin-Bicêtre, , France

University of Leipzig

Leipzig, , Germany

Great Ormond Street Hospital for Children NHS Foundation Trust

London, , United Kingdom

Countries

United States; Argentina; Australia; France; Germany; United Kingdom

References

Eichler F, Duncan CN, Musolino PL, Lund TC, Gupta AO, De Oliveira S, Thrasher AJ, Aubourg P, Kuhl JS, Loes DJ, Amartino H, Smith N, Folloni Fernandes J, Sevin C, Sankar R, Hussain SA, Gissen P, Dalle JH, Platzbecker U, Downey GF, McNeil E, Demopoulos L, Dietz AC, Thakar HL, Orchard PJ, Williams DA. Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2024 Oct 10;391(14):1302-1312. doi: 10.1056/NEJMoa2400442.

Reference Type: DERIVED

PMID: 39383459 (View on PubMed)

Duncan CN, Bledsoe JR, Grzywacz B, Beckman A, Bonner M, Eichler FS, Kuhl JS, Harris MH, Slauson S, Colvin RA, Prasad VK, Downey GF, Pierciey FJ, Kinney MA, Foos M, Lodaya A, Floro N, Parsons G, Dietz AC, Gupta AO, Orchard PJ, Thakar HL, Williams DA. Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2024 Oct 10;391(14):1287-1301. doi: 10.1056/NEJMoa2405541.

Reference Type: DERIVED

PMID: 39383458 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28976817 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.gov/show/NCT02698579

ALD-102 is parent study for LTF-304 study

Other Identifiers

2011-001953-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ALD-102

Identifier Type: -

Identifier Source: org_study_id