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Autologous Cryopreserved CD34+ Hematopoietic Cells Transduced With EFS-ADA Lentivirus for ADA SCID

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ClinicalTrials.gov Identifier: NCT02999984
Recruitment Status : Active, not recruiting
First Posted : December 21, 2016
Last Update Posted : February 11, 2019
Sponsor:
Collaborators:
University College, London
California Institute for Regenerative Medicine (CIRM)
University of California, Los Angeles
Information provided by (Responsible Party):
Orchard Therapeutics

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) LV (Lentiviral Vector) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 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 will be infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who have successfully received the OTL-101 product, PEG-ADA ERT (Enzyme Replacement Therapy) will be 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 Phase 1 Phase 2

Detailed Description:

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 cells transduced ex vivo with EFS LV encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years, who are not eligible for an HLA-matched sibling/family donor and meeting the inclusion/exclusion criteria.

The aim of this clinical study is also to assess the success of treatment at the subject level ("responder analysis") 6 months post OTL-101 infusion, using predictive criteria for overall survival and event free survival and to compare data obtained from clinical studies using the fresh formulation of OTL-101.

Eligible subjects will be hospitalized to undergo the harvesting of autologous CD34+ cells. To enable the release of the cell product for infusion, the product must meet various quality control criteria for safety, identity, viability, purity and potency. If OTL-101 meets the acceptance criteria and is released, the subjects will be readmitted for conditioning prior to infusion of OTL-101.

For subjects who have successfully received the OTL-101 product, PEG-ADA ERT will be 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 at Months 1, 3, 6, 9, 12, 18, and 24. Any medically-indicated interventions will be determined at these visits. After Month 24 visit, the subjects will have completed the study and may enter a long term registry.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Cryopreserved Formulation of Autologous CD34+ Hematopoietic Stem Cells Transduced Ex Vivo With EFS Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency Due to ADA Deficiency
Actual Study Start Date : December 16, 2016
Actual Primary Completion Date : October 11, 2018
Estimated Study Completion Date : October 2019


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
Infusion of OTL-101 after reduced intensity conditioning
Other Name: OTL-101




Primary Outcome Measures :
  1. The number of subjects with treatment success post OTL-101 infusion [ Time Frame: 6 Months ]

    Defined as meeting or exceeding the threshold for all three of the following parameters:

    1. Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),
    2. Evidence of immune reconstitution as measured by absolute number of CD3 cells ≥200/mm3),
    3. Detectable gene-marked granulocytes as measured by differential polymerase chain reaction (dPCR)/ quantitative PCR (qPCR) (≥1/10,000 cells).

  2. Overall survival [ Time Frame: 12 Months ]
    Overall survival is defined as the proportion of subjects alive.

  3. Event free survival [ 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 allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 24 months ]
    Overall survival is defined as the proportion of subjects alive.

  2. Event free survival [ 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 allogenic HSCT, or death.



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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:

    Evidence of ADA deficiency, defined as:

    i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal 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,

    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 (ALC) <400 cells/µL) OR absence or low number of T cells (absolute CD3+ count < 300 cells/µL), 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 matched family 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 HSCT as per clinical site criteria.
  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. Hematologic abnormality, defined as:

    • Anemia (Hb <8.0 g/dl).
    • Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility.
    • Thrombocytopenia (platelet count <50,000/mm3, at any age).
    • Prothrombin time or international normalized ratio (INR) and 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 on peripheral blood or bone marrow or amniotic fluid (if available).
    • Prior allogeneic 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. Renal abnormality, defined as:

    • Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or ≥3+ proteinuria.
    • Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at >2 x ULN.
  8. Hepatic/gastrointestinal abnormality, defined as:

    • Serum transaminases >5 x ULN.
    • Serum bilirubin >2 x ULN.
    • Serum glucose >1.5 x ULN.
  9. Oncologic disease, defined as:

    • Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP).
    • 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) PCR positive at time of screening assessment for the following:

    • HIV-1,
    • Hepatitis B,
    • Parvovirus B19.
  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): NCT02999984


Locations
United States, California
University of California, Los Angeles
Los Angeles, California, United States, 90095
Sponsors and Collaborators
Orchard Therapeutics
University College, London
California Institute for Regenerative Medicine (CIRM)
University of California, Los Angeles
Investigators
Study Director: Donald B. Kohn, MD University of California, Los Angeles

Additional Information:
Publications:
Responsible Party: Orchard Therapeutics
ClinicalTrials.gov Identifier: NCT02999984     History of Changes
Other Study ID Numbers: OTL-101-4
First Posted: December 21, 2016    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Severe Combined Immunodeficiency
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases