Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene

NCT01852071 | Completed Phase 1 Results DMC FDA Drug

• 4 other identifiers: EFS-ADAU01AI1008012P01HL0731040910-1006
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 2

Brief Summary

The aim of this study is to assess the safety and efficacy of autologous transplantation of hematopoietic stem cells (CD34+ cells) from the bone marrow (BM) of ADA-deficient SCID infants and children following human ADA cDNA transfer by the EFS-ADA lentiviral vector. The level of gene transfer in blood cells and immune function will be measured as endpoints.

Conditions

ADA-SCID

Keywords

gene therapy; hematopoietic stem cell; ADA-SCID; lentiviral vector

Outcome Measures

Primary Outcomes (2)

• Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)

  Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101 or HSCT

  12 months

• Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)

  Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogeneic Hematopoietic Stem Cell Transplant (HSCT), or death.

  12 months

Secondary Outcomes (9)

• OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)

  24 months

• EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)

  24 months

• Vector Copy Number (VCN) in Peripheral Blood (PB) Granulocytes.

  24 months

• VCN in Peripheral Blood Mononuclear Cells (PBMCs)

  24 months

• ADA Activity in Erythrocytes

  24 months

Study Arms (1)

Gene Therapy

EXPERIMENTAL

Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells

Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101); Drug: busulfan; Drug: PEG-ADA ERT

Interventions

Infusion of autologous EFS-ADA LV CD34+ (OTL-101) GENETIC

autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously

Also known as: OTL-101

Gene Therapy

busulfan DRUG

Busulfan is used for non-myeloablative conditioning

Gene Therapy

PEG-ADA ERT DRUG

PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Gene Therapy

Eligibility Criteria

• Age: 1 Month - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or confirmed ADA gene mutation(s) known to cause disease , AND
• B. Evidence of severe combined immunodeficiency based on either:
• Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR
• Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on
• lymphopenia (absolute lymphocyte count \<400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count \<300 cells/mcL) OR
• severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either \<10% of lower limit of normal controls for the diagnostic laboratory, \<10% of the response of the normal control of the day, or stimulation index \<10)
• Ineligible for matched sibling allogeneic bone marrow transplantation: absence of a medically eligible HLA-identical sibling, with normal immune function, who may serve as an allogeneic bone marrow donor
• Signed written informed consent according to guidelines of the Institutional Review Board (IRB) (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) IRB

You may not qualify if:

• Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days of entering this trial.
• Hematologic
• Anemia (hemoglobin \< 10.5 g/dl at \< 2 years of age, or \< 11.5 g/dl at \> 2 years of age).
• Neutropenia (absolute granulocyte count \<500/mm3.
• Thrombocytopenia (platelet count \< 150,000/mm3, at any age).
• International Normalised Ratio (INR) or Prothrombin Time (PT) \> 2 times the upper limits of normal or Partial Thromboplastin Time (PTT) \> 2.33 times the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded).
• Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
• Prior allogeneic Hematopoietic Stem Cell Transplant (HSCT) with cytoreductive conditioning
• Infectious
• a. Evidence of infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA Polymerase Chain Reaction (PCR) within 90 days prior to bone marrow harvest. If other infection is present, it must be under control (e.g. stable or decreasing viral load) at the time of screening
• Pulmonary
• Resting O2 saturation by pulse oximetry \< 95% on room air.
• Chest x-ray indicating active or progressive pulmonary disease.
• Cardiac
• Abnormal electrocardiogram (EKG) indicating cardiac pathology.

Sponsors & Collaborators

• University of California, Los Angeles: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• National Human Genome Research Institute (NHGRI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Orchard Therapeutics: collaborator

Study Sites (2)

Mattel Children's Hospital, UCLA

Los Angeles, California, 90095, United States

Location

Mark O. Hatfield Clinical Research Center, NIH

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu PY, Gschweng E, Cooper A, Tisdale JF, Weinberg KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu XJ, Smogorzewska M, Wayne AS, Rosenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X, Gjertson D, Yang OO, Balamurugan A, Bauer G, Ireland JA, Engel BC, Podsakoff GM, Hershfield MS, Blaese RM, Parkman R, Kohn DB. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012 Nov 1;120(18):3635-46. doi: 10.1182/blood-2012-02-400937. Epub 2012 Sep 11.

  PMID: 22968453 BACKGROUND

• Carbonaro DA, Zhang L, Jin X, Montiel-Equihua C, Geiger S, Carmo M, Cooper A, Fairbanks L, Kaufman ML, Sebire NJ, Hollis RP, Blundell MP, Senadheera S, Fu PY, Sahaghian A, Chan RY, Wang X, Cornetta K, Thrasher AJ, Kohn DB, Gaspar HB. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014 Mar;22(3):607-622. doi: 10.1038/mt.2013.265. Epub 2013 Nov 20.

  PMID: 24256635 BACKGROUND

• Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.

  PMID: 33974366 DERIVED

MeSH Terms

Conditions

Severe combined immunodeficiency due to adenosine deaminase deficiency

Interventions

Busulfan

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Orchard Medical Information
• Organization: Orchard Therapeutics (Europe) Ltd

medinfo@orchard-tx.com

+44 (0) 203 808 8286

Study Officials

• Donald B Kohn, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 7, 2013
• First Posted: May 13, 2013
• Study Start: August 2, 2013
• Primary Completion: August 27, 2018
• Study Completion: August 27, 2018
• Last Updated: August 3, 2022
• Results First Posted: September 20, 2021

Record last verified: 2022-08

Locations

US (2)