Clinical trial NCT01896102: A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Cerebral Adrenoleukodystrophy (CALD)
Keywords: Adrenoleukodystrophy
X-linked adrenoleukodystrophy
Gene therapy
Hematopoietic stem cell
Lead sponsor: bluebird bio
Sponsor class: INDUSTRY
First posted: 2013-07-11
Enrollment: 32
Sex: MALE
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24 and Without Allo-HSCT or Rescue Cell Administration
timeFrame: At Month 24
measure: Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24
timeFrame: By Month 24
Secondary outcomes:
measure: Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24
timeFrame: At Month 24
measure: Time to Sustained Resolution of Gadolinium Positivity on MRI
timeFrame: Up to Month 24
measure: Number of Participants With Change in Total Neurologic Function Score (NFS) From Baseline up to Month 24
timeFrame: Baseline up to 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: Proportion of Participants With Neutrophil Engraftment by 42 Days Post-drug Product Infusion
timeFrame: By 42 days post-drug infusion
measure: Time to Neutrophil Engraftment Post-drug Product Infusion
timeFrame: By 42 days post-drug infusion
measure: Proportion 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: Proportion of Participants With Engraftment Failure By Month 24
timeFrame: By Month 24
measure: Proportion of Participants Who Underwent a Subsequent Allo-Hematopoietic Stem Cell (HSC) Infusion by Month 24
timeFrame: By Month 24
measure: Percentage of Participants With 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 Adverse Events (AEs), Serious AEs, Grade >=3 AE, Related AEs, Related SAEs and Related Grade >=3 AEs
timeFrame: From date of informed consent up to Month 24
measure: Percentage of Participants With Potentially Clinical Significant Changes in Laboratory Parameters by Month 24
timeFrame: From time of drug product infusion up 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: 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 With 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center
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: Buenos Aires
country: Argentina
facility: Medeos SRL
city: North Adelaide
country: Australia
facility: Women and Children's Hospital
state: South Australia
city: Le Kremlin-Bicêtre Cedex
country: France
facility: Hôpital Bicêtre
city: Leipzig
country: Germany
facility: University of Leipzig
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
Study officials:
affiliation: bluebird bio, Inc.
name: Jakob Sieker, MD.
role: STUDY_DIRECTOR
affiliation: Boston Children's Hospital
name: David Williams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Christine Duncan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Florian Eichler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Satiro de Oliveira, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Paul Orchard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Ormond Street Hospital for Chidren NHS Foundation Trust
name: Adrian Thrasher, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Bicêtre
name: Patrick Aubourg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Leipzig
name: Jorn-Sven Kuhl, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Women and Children's Hospital
name: Nicholas Smith, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medeos SRL
name: Hernan Amartino, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.