Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03765632
Recruitment Status : Recruiting
First Posted : December 5, 2018
Last Update Posted : May 28, 2020
Sponsor:
Collaborator:
Orchard Therapeutics
Information provided by (Responsible Party):
Great Ormond Street Hospital for Children NHS Foundation Trust

Brief Summary:
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of >/=30 days and <18 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety.

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency Due to ADA Deficiency Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) Drug: Busulfan Drug: Peg-Ada Phase 1 Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of a Cryopreserved Formulation of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1α Short Form (EFS) Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency (SCID) Due to Adenosine Deaminase Deficiency
Actual Study Start Date : January 3, 2018
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: Gene Therapy
Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
Genetic: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101)
Autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Name: OTL-101

Drug: Busulfan
Busulfan is used for non-myeloablative conditioning

Drug: Peg-Ada
Peg-Ada Enzyme Replacement Therapy (ERT) is discontinued at Day +30 (-3/+15 days) after successful engraftment




Primary Outcome Measures :
  1. Overall survival at 12 months post OTL-101 infusion [ Time Frame: 12 Months ]
    Overall survival is defined as the proportion of subjects alive

  2. Event free survival at 12 months post OTL-101 infusion [ Time Frame: 12 Months ]
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death


Secondary Outcome Measures :
  1. Overall survival at 24 months post OTL-101 infusion [ Time Frame: 24 months ]
    Overall survival is defined as the proportion of subjects alive

  2. Event free survival at 24 months post OTL-101 infusion [ Time Frame: 24 Months ]
    Event-free survival is defined as the proportion of subjects alive with no "event", an "event" being the resumption of Peg-Ada ERT or the need for a rescue stem cell transplant (SCT), or death

  3. Safety evaluation including infection rates [ Time Frame: 12 and 24 months ]
  4. Safety evaluation including performance outcomes [ Time Frame: 12 and 24 months ]
  5. Safety evaluation including immune reconstitution [ Time Frame: 12 and 24 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child
  2. Subjects ≥30 days and <18 years of age,
  3. With a diagnosis of ADA-SCID based on:

    1. . Evidence of ADA deficiency, defined as: i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured foetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,
    2. . Evidence of ADA-SCID based on either: i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on

    Lymphopenia (absolute lymphocyte count <400 cells/mL) OR absence or low number of T-cells (absolute CD3+ count < 300 cells/mL), or

    Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, or <10% of the response of the normal control of the day, or stimulation index <10), or

    Identification of SCID by neonatal screening revealing low T cell Receptor Excision Circle (TREC) levels.

  4. Ineligible for or with no available matched family donor for allogeneic Bone Marrow (BM) transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.
  5. Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.
  6. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

  1. Ineligible for autologous hematopoietic stem cell (HSC) procedure.
  2. Other conditions which in the opinion of the Principal Investigator and/or Co-Investigators, contraindicate the harvest of bone marrow, the administration of Busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol.
  3. Haematologic abnormality, defined as:

    Anaemia (Hb <8.0 g/dl). Evidence of bi/trilineage cytopaenia (haemoglobin <8 g/dl, neutrophils <0.5 x 109/L, platelets 50 x 109/L). Thrombocytopaenia (platelet count <50,000/mm3). Prothrombin time or partial thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).

    • Cytogenetic abnormalities of Peripheral Blood (PB), BM or amniotic fluid (if available). If cytogenetic testing has not been performed on cells from amniocentesis, assessment should be by karyotype, Comparative genomic hybridization (CGH), and or whole exome sequencing (WES).
    • Prior allogeneic HSC transplant (HSCT) with cytoreductive conditioning.
  4. Pulmonary abnormality, defined as:

    • Resting O2 saturation by pulse oximetry <90% on room air.
    • Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X-ray indicating residual signs of treated pneumonitis is acceptable for eligibility.
  5. Cardiac abnormality, defined as:

    • Abnormal ECG indicating cardiac pathology.
    • Uncorrected congenital cardiac malformation with clinical symptoms.
    • Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
    • Poor cardiac function as evidenced by left ventricular ejection fraction <40% on echocardiogram.
  6. Neurologic abnormality, defined as:

    • Significant neurologic abnormality revealed by examination.
    • Uncontrolled seizure disorder.
  7. Known history of significant renal abnormality.
  8. Known history of significant hepatic or gastrointestinal abnormality.
  9. Oncologic disease, defined as:

    • Evidence of active malignant disease other than Dermatofibrosarcoma Protuberans( DFSP) 2.
    • Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells (if anti-neoplastic therapy has been completed, a subject with a history of DFSP can be included).
    • Evidence of DFSP expected to be life-limiting within the 5 years following the infusion of genetically corrected cells.
  10. Known sensitivity to Busulfan.
  11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) polymerase chain reactions (PCR) positive at time of screening assessment according to local protocols/procedures (including HIV-1 and hepatitis B).
  12. The subject is pregnant or has a major congenital anomaly.
  13. Is likely to require treatment during the study with drugs that are not permitted by the study protocol.
  14. The subject has previously received another form of gene therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03765632


Contacts
Layout table for location contacts
Contact: Claire Booth, Dr +44 (0)207 905 2198 c.booth@ucl.ac.uk

Locations
Layout table for location information
United Kingdom
Great Ormond Street Hospital for Children NHS Foundation Trust Recruiting
London, United Kingdom, WC1N 3JH
Contact: Claire Booth, Dr    +44 (0) 207 905 2198    C.Booth@ucl.ac.uk   
Contact: Kajal Soni    +44 (0) 207 762 6056    k.soni@ucl.ac.uk   
Principal Investigator: Claire Booth, Dr         
Sponsors and Collaborators
Great Ormond Street Hospital for Children NHS Foundation Trust
Orchard Therapeutics
Investigators
Layout table for investigator information
Principal Investigator: Claire Booth, Dr Great Ormond Street Hospital NHS Foundation Trust
Layout table for additonal information
Responsible Party: Great Ormond Street Hospital for Children NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03765632    
Other Study ID Numbers: OTL-101-5
First Posted: December 5, 2018    Key Record Dates
Last Update Posted: May 28, 2020
Last Verified: May 2020

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Great Ormond Street Hospital for Children NHS Foundation Trust:
Gene therapy
Hematopoietic stem and progenitor cells
Lentiviral vector
ADA-SCID
Additional relevant MeSH terms:
Layout table for MeSH terms
Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists